Challenges in IBD Research 2024: Novel Technologies.

Novel technology is one of the five focus areas of the Challenges in Inflammatory Bowel Disease (IBD) Research 2024 document. Building off the Challenges in IBD Research 2019 document, the Foundation aims to provide a comprehensive overview of current gaps in IBD research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in interception, remission, and restoration for these diseases. The document is the result of a multidisciplinary collaboration from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. Specifically, the Novel Technologies section focuses on addressing key research gaps to enable interception and improve remission rates in IBD. This includes testing predictions of disease onset and progression, developing novel technologies tailored to specific phenotypes, and facilitating collaborative translation of science into diagnostics, devices, and therapeutics. Proposed priority actions outlined in the document include real-time measurement of biological changes preceding disease onset, more effective quantification of fibrosis, exploration of technologies for local treatment of fistulas, and the development of drug delivery platforms for precise, location-restricted therapies. Additionally, there is a strong emphasis on fostering collaboration between various stakeholders to accelerate progress in IBD research and treatment. Addressing these research gaps necessitates the exploration and implementation of bio-engineered novel technologies spanning a spectrum from materials to systems. By harnessing innovative ideas and technologies, there's a collective effort to enhance patient care and outcomes for individuals affected by IBD.

Technology drives medical progress, solving clinical challenges and enhancing patient care in inflammatory bowel disease (IBD). Collaborative efforts focus on addressing research gaps to improve interception, restoration, and remission rates, utilizing innovative technologies for better patient outcomes.

Use of Biologics for the Treatment of Inflammatory Conditions of the Pouch: A Systematic Review.

BACKGROUND: Patients with medically-refractory ulcerative colitis or advanced neoplasia are often offered an ileal-pouch-anal anastomosis to restore bowel continuity. However, up to 50% of patients can suffer from inflammatory conditions of the pouch, some of which require biological therapy to treat. The aim of this study was to determine the efficacy of each biological agent for the treatment of inflammatory conditions of the pouch. MATERIALS AND METHODS: A comprehensive literature search was performed in the major databases from inception through February 11, 2020, for studies assessing the efficacy of biologics in chronic antibiotic-refractory pouchitis (CARP) and Crohn's disease (CD) of the pouch. Both prospective and retrospective studies were included. The primary outcomes of interest were complete and partial responses were defined within each study. χ 2 test was used to compare variables. RESULTS: Thirty-four studies were included in the systematic review and meta-analysis. Sixteen studies (N=247) evaluated the use of infliximab (IFX), showing complete response in 50.7% and partial response in 28.1% for CARP, and complete response in 66.7% and partial response in 20% for CD of the pouch. Seven studies (n=107) assessed the efficacy of adalimumab. For CARP, 33.3% of patients had a complete response, and 38.1% had a partial response, whereas for CD of the pouch, 47.7% experienced a complete response, and 24.6% had a partial response. Three studies (n=78) reported outcomes with the use of ustekinumab, showing 50% complete response and 3.8% partial response for CARP. For the CD of the pouch, 5.8% had a complete response and 78.8% had a partial response. Seven studies (n=151) reported the efficacy of vedolizumab, showing 28.4% complete response and 43.2% partial response in patients with CARP, whereas 63% of patients experienced partial response in CD of the pouch. IFX had higher rates of complete response in CARP compared with adalimumab ( P =0.04) and compared with vedolizumab ( P =0.005), but not compared with ustekinumab ( P =0.95). There were no new safety signals reported in any of the studies. CONCLUSIONS: Biologics are safe and efficacious in the treatment of chronic, refractory inflammatory conditions of the pouch. IFX seems to be more efficacious than adalimumab and vedolizumab for CARP. Further prospective, head-to-head evaluations are needed to compare biological therapies in the treatment of CARP and CD of the pouch.

PSMA-Targeted PET Radiotracer [18F]DCFPyL as an Imaging Biomarker in Inflammatory Bowel Disease.

Background: Prostate-specific membrane antigen (PSMA) is highly and specifically upregulated in active-inflamed mucosa of patients with inflammatory bowel disease (IBD). We hypothesized that this upregulation would be detectable using a PSMA-targeted positron emission tomography/computed tomography (PET/CT) imaging agent, [18F]DCFPyL, enabling non-invasive visualization of inflammation. A noninvasive means of detecting active inflammation would have high clinical value in localization and management of IBD. Study: We performed [18F]DCFPyL imaging in three IBD patients with active disease. Abnormally increased gastrointestinal [18F]DCFPyL uptake was observed in areas with endoscopic, histologic, and immunohistochemical inflammation, demonstrating partial overlap of segments of bowel with abnormal [18F]DCFPyL uptake and active inflammation. Conclusion: This study demonstrates that PSMA-targeted [18F]DCFPyL PET can effectively detect regions of inflamed mucosa in patients with IBD, suggesting its utility as a non-invasive imaging agent to assess location, extent, and disease activity in IBD.

Untethered shape-changing devices in the gastrointestinal tract.

INTRODUCTION: Advances in microfabrication, automation, and computer engineering seek to revolutionize small-scale devices and machines. Emerging trends in medicine point to smart devices that emulate the motility, biosensing abilities, and intelligence of cells and pathogens that inhabit the human body. Two important characteristics of smart medical devices are the capability to be deployed in small conduits, which necessitates being untethered, and the capacity to perform mechanized functions, which requires autonomous shape-changing. AREAS COVERED: We motivate the need for untethered shape-changing devices in the gastrointestinal tract for drug delivery, diagnosis, and targeted treatment. We survey existing structures and devices designed and utilized across length scales from the macro to the sub-millimeter. These devices range from triggerable pre-stressed thin film microgrippers and spring-loaded devices to shape-memory and differentially swelling structures. EXPERT OPINION: Recent studies demonstrate that when fully enabled, tether-free and shape-changing devices, especially at sub-mm scales, could significantly advance the diagnosis and treatment of GI diseases ranging from cancer and inflammatory bowel disease (IBD) to irritable bowel syndrome (IBS) by improving treatment efficacy, reducing costs, and increasing medication compliance. We discuss the challenges and possibilities associated with ensuring safe, reliable, and autonomous operation of these smart devices.

Extracellular Vesicles in Hepatocellular Carcinoma: Progress and Challenges in the Translation from the Laboratory to Clinic.

Extracellular vesicles (EVs) play critical roles in intercellular communication by transporting bioactive cargo to recipient cells. EVs have been implicated in a range of physiological and pathological processes, including tumor progression, metastasis, immune modulation, and drug resistance. The objective of this review is to present a thorough overview of recent studies focusing on EVs in hepatocellular carcinoma (HCC), with an emphasis on their potential utility as diagnostic biomarkers as well as therapeutic agents. Initially, we explore the utility of EVs as diagnostic biomarkers for HCC, followed by a discussion of their potential as carriers of therapeutic payloads. Additionally, we delve into the emerging field of therapeutic EVs for modulating tumor immune responses. Through this review, our ultimate aim is to provide a comprehensive understanding of the opportunities and challenges in the clinical translation of EV research in the domain of HCC.

Antibody Kinetics after Three Doses of SARS-CoV-2 mRNA Vaccination in Patients with Inflammatory Bowel Disease.

Background: The emergence of new SARS-CoV-2 variants calls for more data on SARS-CoV-2 mRNA vaccine response. Aims: We aimed to assess the response to a third mRNA vaccine dose against SARS-CoV-2 in inflammatory bowel disease (IBD) patients. Methods: This was a single-center, observational prospective study of IBD patients who received a third mRNA vaccine dose against SARS-CoV-2. Antibody titers were taken post-third-dose at one and three months using the Roche Elecsys anti-SARS-CoV-2-S enzyme immunoassay. Titers less than 0.8 units/mL were considered negative according to the manufactures. Titers between 0.8 units/mL and 250 units/mL were considered non-neutralizing. Titers greater than 250 units/mL were considered neutralizing. Results: Eighty-three patients were included, all of whom had detectable antibodies at 3 months post-third dose. A total of 89% showed neutralizing and 11% non-neutralizing titers. Participants with non-neutralizing titers were more likely to be on systemic corticosteroids (p = 0.04). Two participants seroconverted from negative to positive, whereas 86% with non-neutralizing titers boosted to neutralizing levels. Only one participant with neutralizing titers after a third dose had a decrease to a non-neutralizing level within 3 months. Conclusions: Our findings support the ongoing recommendations for additional doses in immunocompromised individuals. However, longitudinal studies with a greater-sized patient population are needed.

Non-Viral Gene Delivery to Hepatocellular Carcinoma via Intra-Arterial Injection.

Purpose: Hepatocellular carcinoma (HCC) has limited treatment options, and modest survival after systemic chemotherapy or procedures such as transarterial chemoembolization (TACE). There is therefore a need to develop targeted therapies to address HCC. Gene therapies hold immense promise in treating a variety of diseases, including HCC, though delivery remains a critical hurdle. This study investigated a new approach of local delivery of polymeric nanoparticles (NPs) via intra-arterial injection for targeted local gene delivery to HCC tumors in an orthotopic rat liver tumor model. Methods: Poly(beta-amino ester) (PBAE) nanoparticles were formulated and assessed for GFP transfection in N1-S1 rat HCC cells in vitro. Optimized PBAE NPs were next administered to rats via intra-arterial injection with and without orthotopic HCC tumors, and both biodistribution and transfection were assessed. Results: In vitro transfection of PBAE NPs led to >50% transfected cells in adherent and suspension culture at a variety of doses and weight ratios. Administration of NPs via intra-arterial or intravenous injection demonstrated no transfection of healthy liver, while intra-arterial NP injection led to transfection of tumors in an orthotopic rat HCC model. Conclusion: Hepatic artery injection is a promising delivery approach for PBAE NPs and demonstrates increased targeted transfection of HCC tumors compared to intravenous administration, and offers a potential alternative to standard chemotherapies and TACE. This work demonstrates proof of concept for administration of polymeric PBAE nanoparticles via intra-arterial injection for gene delivery in rats.

A combination therapy of bortezomib, CXCR4 inhibitor, and checkpoint inhibitor is effective in cholangiocarcinoma in vivo.

Cholangiocarcinoma (CCA) is a biliary tree malignancy with a dismal prognosis. Tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) has been shown to be involved in drug resistance. To model the interactions between cancer cells and the TME, we established CCA complex patient-derived organoids (cPDOs) to include epithelial PDO (ePDOs) and matched CAFs. While ePDOs were sensitive to bortezomib, we found the matched cPDOs were relatively resistant. Mechanistically, this resistance was correlated with over-expression of CXCR4 in the CAF component of cPDOs. In accord with the role of CXCR4 in the resistance to bortezomib, we found that a CXCR4 inhibitor can reverse the resistance to bortezomib in vivo. Furthermore, we found that the inhibition of CXCR4 allowed bortezomib to sensitize CCA to anti-PD1 treatment, with a significant reduction of tumor burden and long-term overall survival. This novel cancer/stroma/immune triple treatment holds great promise for the treatment of CCA.

Injectable, Drug-Eluting Nanocrystals Prevent Fibrosis and Stricture Formation In Vivo.

BACKGROUND & AIMS: Tissue fibrosis results from uncontrolled healing responses leading to excessive mesenchymal cell activation and collagen and other extracellular matrix deposition. In the gastrointestinal tract, fibrosis leads to narrowing of the lumen and stricture formation. A drug treatment to prevent fibrosis and strictures in the gastrointestinal tract would be transformational for patient care. We aimed to develop a stricture treatment with the following characteristics and components: a small molecule with strong antifibrotic effects that is delivered locally at the site of the stricture to ensure correct lesional targeting while protecting the systemic circulation, and that is formulated with sustained-release properties to act throughout the wound healing processes. METHODS: A high-throughput drug screening was performed to identify small molecules with antifibrotic properties. Next, we formulated an antifibrotic small molecule for sustained release and tested its antifibrotic potential in 3 animal models of fibrosis. RESULTS: Sulconazole, a US Food and Drug Administration-approved drug for fungal infections, was found to have strong antifibrotic properties. Sulconazole was formulated as sulconazole nanocrystals for sustained release. We found that sulconazole nanocrystals provided superior or equivalent fibrosis prevention with less frequent dosing in mouse models of skin and intestinal tissue fibrosis. In a patient-like swine model of bowel stricture, a single injection of sulconazole nanocrystals prevented stricture formation. CONCLUSIONS: The current data lay the foundation for further studies to improve the management of a range of diseases and conditions characterized by tissue fibrosis.

Adipokine C1q/Tumor Necrosis Factor- Related Protein 3 (CTRP3) Attenuates Intestinal Inflammation Via Sirtuin 1/NF-κB Signaling.

BACKGROUND & AIMS: The adipokine CTRP3 has anti-inflammatory effects in several nonintestinal disorders. Although serum CTRP3 is reduced in patients with inflammatory bowel disease (IBD), its function in IBD has not been established. Here, we elucidate the function of CTRP3 in intestinal inflammation. METHODS: CTRP3 knockout (KO) and overexpressing transgenic (Tg) mice, along with their corresponding wild-type littermates, were treated with dextran sulfate sodium for 6-10 days. Colitis phenotypes and histologic data were analyzed. CTRP3-mediated signaling was examined in murine and human intestinal mucosa and mouse intestinal organoids derived from CTRP3 KO and Tg mice. RESULTS: CTRP3 KO mice developed more severe colitis, whereas CTRP3 Tg mice developed less severe colitis than wild-type littermates. The deletion of CTRP3 correlated with decreased levels of Sirtuin-1 (SIRT1), a histone deacetylase, and increased levels of phosphorylated/acetylated NF-κB subunit p65 and proinflammatory cytokines tumor necrosis factor-α and interleukin-6. Results from CTRP3 Tg mice were inverse to those from CTRP3 KO mice. The addition of SIRT1 activator resveratrol to KO intestinal organoids and SIRT1 inhibitor Ex-527 to Tg intestinal organoids suggest that SIRT1 is a downstream effector of CTRP3-related inflammatory changes. In patients with IBD, a similar CTRP3/SIRT1/NF-κB relationship was observed. CONCLUSIONS: CTRP3 expression levels correlate negatively with intestinal inflammation in acute mouse colitis models and patients with IBD. CTRP3 may attenuate intestinal inflammation via SIRT1/NF-κB signaling. The manipulation of CTRP3 signaling, including through the use of SIRT1 activators, may offer translational potential in the treatment of IBD.

A nanofiber-hydrogel composite improves tissue repair in a rat model of Crohn's disease perianal fistulas.

Perianal fistulas (PAFs) represent a severe complication of Crohn's disease (CD). Despite the advent of biologic and small-molecule therapeutics for luminal disease, PAFs in CD (CD-PAF) are relatively resistant to treatment, with less than 50% responding to any therapy. We report an injectable, biodegradable, mechanically fragmented nanofiber-hydrogel composite (mfNHC) loaded with adipose-derived stem cells (ADSCs) for the treatment of fistulas in a rat model of CD-PAF. The ADSC-loaded mfNHC results in a higher degree of healing when compared to surgical treatment of fistulas, which is a standard treatment. The volume of fistulas treated with mfNHC is decreased sixfold compared to the surgical treatment control. Molecular studies reveal that utilization of mfNHC reduced local inflammation and improved tissue regeneration. This study demonstrates that ADSC-loaded mfNHC is a promising therapy for CD-PAF, and warrants further studies to advance mfNHC toward clinical translation.

Initial Clinical Outcomes Using Umbilical Cord-Derived Tissue Grafts to Repair Anovaginal Fistula.

BACKGROUND: Perianal fistula is a debilitating disease and challenging condition to treat. Recently, the use of stem cells has been shown to improve healing of fistulas. OBJECTIVE: The aim was to examine the use of an umbilical cord-derived stem cell graft in a pilot study as a novel scaffold/stem inlay implanted into fistula repairs for anovaginal fistula to examine healing rates. DESIGN: This was a pilot study. SETTINGS: This study took place in a colorectal surgery practice. PATIENTS: Patients with anovaginal fistula consented to participate. Cryopreserved umbilical cord tissue graft with viable cells was incorporated as an inlay using a previously reported technique by the authors. Demographic data including history of previous repairs and IBD were included. All patients were followed for a minimum of 6 weeks. MAIN OUTCOME MEASURES: The primary measures were safety and efficacy of novel stem cell graft in the treatment of anovaginal fistula. RESULTS: From September 2017 to September 2019, 15 patients underwent anovaginal fistula repair. Three of these patients underwent a second repair, for a total of 18 repairs. No patient was intentionally diverted, but 3 patients presented for repair with a preexisting stoma. The majority of repairs were previous repair failures (12; 67%), and 7 repairs were performed on 5 patients with IBD. Median follow-up was 30 (6-104) weeks. The safety profile for cryopreserved umbilical cord tissue graft was excellent as no adverse events occurred. Overall complete healing rate was 39%, and 12 (67%) repairs resulted in improvement of symptoms. LIMITATIONS: This was a small pilot study. CONCLUSIONS: This is the largest series using cryopreserved umbilical cord graft for anovaginal fistula repair. The use of umbilical cord was safe and effective at closing defects. Randomized studies are necessary to determine added benefits over current standard of care. See Video Abstract at http://links.lww.com/DCR/B896 . RESULTADOS CLNICOS INICIALES DEL USO DE INJERTOS DE TEJIDO DERIVADO DE PLACENTA PARA REPARACIN DE FSTULAS ANOVAGINALES: ANTECEDENTES:La fístula perianal es una enfermedad debilitante y una afección difícil de tratar. Recientemente, se ha demostrado que el uso de células madre mejora la curación de las fístulas.OBJETIVO:Deseamos examinar el uso de un injerto de células madre derivadas de cordón umbilical en un estudio piloto como una nueva matriz/injerto de células madre implantado en reparaciones de fístula para fístula anovaginal para examinar las tasas de curación.DISEÑO:Este fue un estudio piloto.ESCENARIO:Este estudio se llevó a cabo en una clínica de cirugía colorrectal.PACIENTES:Se obtuvo consentimiento informado de pacientes con fístula anovaginal. El injerto de tejido de cordón umbilical criopreservado con células viables se incorporó como incrustación utilizando una técnica previamente informada por los autores. Se incluyeron datos demográficos que incluían antecedentes de reparaciones previas y enfermedad inflamatoria intestinal. Todos los pacientes fueron seguidos durante un mínimo de 6 semanas.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas fueron la seguridad y la eficacia del nuevo injerto de células madre en el tratamiento de la fístula anovaginal.RESULTADOS:Desde 9/2017-9/2019, 15 pacientes fueron sometidas a reparación de fístula anovaginal. Tres de estos pacientes fueron sometidos a una segunda reparación, para un total de 18 reparaciones. Ningún paciente fue derivado intencionalmente mientras que 3 pacientes se presentaron para reparación con un estoma preexistente. La mayoría de las reparaciones fueron fallas de reparaciones previas (12, 67%) y se realizaron siete reparaciones en 5 pacientes con enfermedad inflamatoria intestinal (EII). La mediana de seguimiento fue de 30 semanas (6-104). El perfil de seguridad del injerto de tejido de cordón umbilical criopreservado fue excelente ya que no se produjeron efectos adversos. La tasa general de curación completa fue del 39% y 12 (67%) reparaciones dieron como resultado una mejoría de los síntomas.LIMITACIONES:Este fue un pequeño estudio piloto.CONCLUSIÓNES:Ésta es la serie más grande de utilización de injerto de cordón umbilical criopreservado para la reparación de una fístula anovaginal. La utilización del cordón umbilical resultó segura y eficaz para cerrar defectos. Se necesitan estudios aleatorizados para determinar los beneficios adicionales sobre el estándar de atención actual. Consulte Video Resumen en http://links.lww.com/DCR/B896 . (Traducción-Dr. Jorge Silva Velazco ).

A Novel Patient-like Swine Model of Perianal Crohn's Disease.

BACKGROUND: Perianal Crohn's disease is associated with poor outcomes and high medical costs. It is notoriously difficult to treat despite therapeutic advancements for luminal disease. A large animal model that mimics human perianal disease is needed to test innovative therapies. OBJECTIVE: This study aimed to create a swine model that replicates the inflammatory component and therapeutic challenges found in patients with perianal Crohn's disease. DESIGN: This was an animal preclinical study. SETTINGS: The experiments were performed at the animal laboratory at the Johns Hopkins University. PATIENTS: Four sus scrufus female pigs were included in the study. INTERVENTIONS: Four female pigs underwent creation of 3 surgical perianal fistulas each, 1 rectovaginal and 2 perianal. Size 24 French setons were placed to maintain patency of the fistula tracts for 4 weeks. After removal of the setons, trinitrobenzene sulfonic acid was administered into the fistula tract to create and maintain local inflammation mimicking perianal Crohn's disease. MAIN OUTCOMES MEASURES: An MRI was obtained to assess the fistulas and the pigs were euthanized to review histopathology. RESULTS: Three inflammatory chronic fistula tracts were successfully created in each pig as confirmed by MRI and examination under anesthesia. This is the first report of maintaining patent fistulas in swine 2 weeks after removal of setons. For the first time, we reported that 2 pigs developed branching fistulas and small abscesses reminiscent of human perianal Crohn's disease. The corresponding histopathologic examination found significant chronic active inflammation on standard hematoxylin and eosin staining. LIMITATIONS: The fistulas were surgically induced and did not occur naturally. CONCLUSIONS: A chronic perianal fistula model in pigs that strongly resembles human perianal Crohn's disease was successfully created. This model can be used to test novel therapeutics and techniques to pave the path for human trials. See Video Abstract at http://links.lww.com/DCR/B969 . UN NUEVO MODELO PORCINO SIMILAR A UN PACIENTE DE LA ENFERMEDAD DE CROHN PERIANAL ANTECEDENTES: La enfermedad de Crohn perianal se asocia con malos resultados y altos costos médicos. Es notoriamente difícil de tratar a pesar de los avances terapéuticos para la enfermedad luminal. Se precisa de un modelo animal grande que imite la enfermedad perianal humana para probar terapias innovadoras.OBJETIVO:Nuestro objetivo de este estudio fue crear un modelo porcino que replique el componente inflamatorio y los desafíos terapéuticos que se encuentran en los pacientes con enfermedad de Crohn perianal.DISEÑO:Este fue un estudio preclínico en animales.AJUSTES:Los experimentos se realizaron en el laboratorio de animales de la Universidad Johns Hopkins.PACIENTES:Se incluyeron en el estudio cuatro cerdas sus scrofa.INTERVENCIONES:Cuatro cerdas fueron sometidas a la creación de 3 fístulas perianales quirúrgicas cada una: 1 recto vaginal y 2 perianales. Se colocaron sedales de 24 French para mantener la permeabilidad de los trayectos fistulosos durante 4 semanas. Tras el retiro de los sedales, se administró ácido trinitrobenceno sulfónico en el trayecto de la fístula para crear y mantener la inflamación local simulando la enfermedad de Crohn perianal.PRINCIPALES MEDIDAS DE RESULTADOS:Se obtuvo una resonancia magnética para evaluar las fístulas y los cerdos fueron sacrificados para revisar la histopatología.RESULTADOS:Se crearon de manera exitosa tres trayectos fistulosos inflamatorios crónicos en cada cerdo, confirmados por imágenes de resonancia magnética y examen bajo anestesia. Este es el primer informe de preservación de fístulas permeables en cerdos 2 semanas tras el retiro de los setones. Por primera vez, informamos que dos cerdos desarrollaron fístulas ramificadas y pequeños abscesos que recuerdan a la enfermedad de Crohn perianal humana. El examen histopatológico correspondiente encontró una significativa inflamación crónica activa en la tinción estándar de hematoxilina y eosina.LIMITACIONES:Las fístulas se indujeron quirúrgicamente y no se produjeron de forma natural.CONCLUSIONES:Se logro recrear con éxito un modelo de fístula perianal crónica en cerdos que se asemeja mucho a la enfermedad de Crohn perianal humana. Este modelo se puede utilizar para probar nuevas terapias y técnicas para allanar el camino para los ensayos en humanos. Consulte Video Resumen en http://links.lww.com/DCR/B969 . (Traducción-Dr Osvaldo Gauto).

Autonomous Untethered Microinjectors for Gastrointestinal Delivery of Insulin.

The delivery of macromolecular drugs via the gastrointestinal (GI) tract is challenging as these drugs display low stability as well as poor absorption across the intestinal epithelium. While permeation-enhancing drug delivery methods can increase the bioavailability of low molecular weight drugs, the effective delivery of high molecular weight drugs across the tight epithelial cell junctions remains a formidable challenge. Here, we describe autonomous microinjectors that are deployed in the GI tract, then efficiently penetrate the GI mucosa to deliver a macromolecular drug, insulin, to the systemic circulation. We performed in vitro studies to characterize insulin release and assess the penetration capability of microinjectors and we measured the in vivo release of insulin in live rats. We found that the microinjectors administered within the luminal GI tract could deliver insulin transmucosally to the systemic circulation at levels similar to those with intravenously administered insulin. Due to their small size, tunability in sizing and dosing, wafer-scale fabrication, and parallel, autonomous operation, we anticipate that these microinjectors will significantly advance drug delivery across the GI tract mucosa to the systemic circulation in a safe manner.

Biostimulatory Micro-Fragmented Nanofiber-Hydrogel Composite Improves Mesenchymal Stem Cell Delivery and Soft Tissue Remodeling.

Functional microgels are preferred stem cell carriers due to the ease of delivery through minimally invasive injection and seamless integration with the surrounding host tissue. A biostimulatory nanofiber-hydrogel composite (NHC) has been previously developed through covalently crosslinking a hyaluronic acid hydrogel network with surface-functionalized poly (ε-caprolactone) nanofiber fragments. The NHC mimics the microarchitecture of native soft tissue matrix, showing enhanced cell infiltration, immunomodulation, and proangiogenic properties. Here, injectability of the pre-formed NHC is improved by mechanical fragmentation, making it into micro-fragmented NHC (mfNHC) in a granular gel form as a stem cell carrier to deliver mesenchymal stem cells (MSCs) for soft tissue remodeling. The mfNHC shows a similar storage modulus but a significantly reduced injection force, as compared with the corresponding bulk NHC. When injected subcutaneously in a rat model, mfNHC-MSC constructs initiate an elevated level of host macrophage infiltration, more pro-regenerative polarization, and subsequently, improved angiogenesis and adipogenesis response when compared to mfNHC alone. A similar trend of host cell infiltration and pro-angiogenic response is detected in a swine model with a larger volume injection. These results suggest a strong potential for use of the mfNHC as an injectable carrier for cell delivery and soft tissue remodeling.

Patient-derived functional organoids as a personalized approach for drug screening against hepatobiliary cancers.

Patient-derived organoids (PDOs) established from hepatobiliary cancers are seen as valuable models of the cancer of origin. More precisely, PDOs have the ability to retain the original cancer genetic, epigenetic and phenotypic features. By extension, hepatobiliary cancer PDOs have the potential to (1) increase our understanding of cancer biology; (2) allow high-throughput drug screening for more efficient identification and testing of small molecule therapeutics, and (3) permit the design of personalized drug choice approaches for patients with liver cancer. Here, we review general principles for PDO establishment from hepatocellular carcinoma and cholangiocarcinoma, their utilization in drug screening strategies, and last, the establishment of complex PDOs to include tumor stroma. We conclude that PDOs represent a promising and important development in investigating interaction between liver cancer cell types and their microenvironment, as well as for positioning PDOs for high throughput drug screening for hepatobiliary cancers, and that further work is now needed to fully realize their potential.

Quaternary nanoparticles enable sustained release of bortezomib for hepatocellular carcinoma.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related mortality in the world. Over the past two decades, there has been minimal improvement in therapies as well as clinical outcomes for patients with Barcelona Clinic Liver Cancer (BCLC)-B. These patients are treated with local interventions, including transarterial chemoembolization. Current methodologies only allow sustained intratumoral release measured in hours. Methodologies to allow sustained local release of the drug cargo over days to weeks are acutely needed. We hypothesize that tumor response as well as outcomes of patients with BCLC-B can be improved through utilization of a highly cytotoxic agent delivered with a sustained release platform. APPROACH AND RESULTS: High-throughput drug screening across 40 HCC patient-derived organoids identified bortezomib (BTZ) as a highly cytotoxic small molecule for HCC. We designed and manufactured sustained release BTZ nanoparticles (BTZ-NP) using a flash nanocomplexation/nanoprecipitation process. We quantified the release profile and tested the anti-tumoral effects in vivo. The BTZ-NP formulation demonstrated a sustained release of BTZ of 30 days. This BTZ-NP formulation was highly effective in controlling tumor size and improved survival in vivo in three animal models of HCC, including when delivered via the hepatic artery, as we envision its delivery in patients. In addition, the BTZ-NP formulation was superior to treatment with doxorubicin-drug eluting beads. CONCLUSIONS: The BTZ-NP formulation provides a potent and safe treatment of HCC via a localized delivery approach. These results warrant additional preclinical studies to advance this technology to human clinical trials.

Antibody Response 3 Months After 2-Dose SARS-CoV-2 mRNA Vaccination in Patients With Inflammatory Bowel Disease.

INTRODUCTION: The response to SARS-CoV-2 vaccination of patients with inflammatory bowel disease (IBD) on immune-modifying therapies requires further investigation because previous studies indicate that patients on immune therapy might have decreased antibody concentrations. METHODS: We present the antireceptor binding domain antibody response over a period of 3 months in 217 patients with IBD who completed standard 2-dose SARS-CoV-2 mRNA vaccine series. RESULTS: Almost all (98.6%) IBD vaccine recipients had a positive antireceptor binding domain antibody response at least 3 months after vaccination. Decreased antibody titers at 3 months were seen in a subset of patients on antitumor necrosis factor-alpha. Approximately 10% of the participants with high-titer antibodies at 1 month had a decrease to low-positive titers at 3 months, which was mostly observed in those on combination therapy and antitumor necrosis factor-alpha monotherapy. DISCUSSION: Larger longitudinal studies are required to define the response in IBD population and its clinical impact.

Hepatobiliary tumor organoids for personalized medicine: a multicenter view on establishment, limitations, and future directions.

Reliable establishment of tumor organoids is paramount to advance applications of organoid technology for personalized medicine. Here, we share our multi-center experience on initiation and tumorigenic confirmation of hepatobiliary cancer organoids. We discuss current concerns, propose potential solutions, and provide future perspectives for improvements in hepatobiliary cancer organoid establishment.

Prognostic Value of Lymph Node Ratio in Patients with Resected Synchronous Colorectal Liver Metastases and Less Than 12 Examined Lymph Nodes.

BACKGROUND: Recent studies suggest that lymph node ratio (LNR) has significantly better prognostic power than N-status in patients with colorectal cancer, in particular when the number of evaluated lymph nodes (LNs) was insufficient. The aim of this study was to assess the prognostic value of LNR in patients with resected synchronous colorectal liver metastases (SCLMs) and less than 12 examined LNs. METHODS: A prospectively maintained database of patients with resected SCLMs was queried for patients with less than 12 LNs evaluated at the time of surgery. X-tile software was used to determine the LNR cutoff value able to divide the patients in two subgroups with distinct prognosis. Overall survival (OS) and disease-free survival (DFS) rates were compared by log-rank test. A multivariate Cox regression analysis identified independent prognostic factors. RESULTS: A cutoff LNR value of 0.22 divided patients into Low-LNR group (35 patients) and High-LNR group (36 patients). Both OS and DFS rates were significantly higher in Low-LNR group than those in High-LNR group. Independent predictors of poor OS were High-LNR (HR: 2.841, 95% CI: 1.480-5.453, p value = 0.002), bilobar SCLMs (HR: 2.253, 95% CI: 1.144-4.437, p value = 0.019) and lack of adjuvant chemotherapy (HR: 2.702, 95% CI: 1.448-5.043, p value = 0.002), while the only independent predictor of poor DFS was High-LNR (HR: 2.531, 95% CI: 1.259-5.090, p value = 0.009). CONCLUSIONS: LNR > 0.22 was independently associated with poor OS and DFS in patients with resected SCLMs and less than 12 evaluated LNs.