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More than three decades ago, we embarked on a number of bioengineering explorations using the most advanced materials and fabrication methods. In every area we ventured into, it was our intention to ensure fundamental discoveries were deployed into the clinic to benefit patients. When we embarked on this journey, we did so without a road map, not even a compass, and so the path was arduous, sometimes tedious. Now, we can see the doorway to deployment on the near horizon. We now appreciate that overcoming the challenges has made this a rewarding and exciting journey. However, maybe we could have been here a lot sooner, and so maybe the lessons we have learned could benefit others and accelerate progress in clinical translation. Through a number of case studies, including neural regeneration, cartilage regeneration, skin regeneration, the 3D printing of capsules for islet cell transplantation, and the bioengineered cornea, here, we retrace our steps. We will summarise the journey to date, point out the obstacles encountered, and celebrate the translational impact. Then, we will provide a framework for project design with the clinical deployment of bioengineered products as the goal.

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Transdermal administration remains an active research and development area as an alternative route for long-acting drug delivery. It avoids major drawbacks of conventional oral (gastrointestinal side effects, low drug bioavailability, and need for multiple dosing) or parenteral routes (invasiveness, pain, and psychological stress and bio-hazardous waste generated from needles), thereby increasing patient appeal and compliance. This review focuses on the current state of long-acting transdermal drug delivery, including adhesive patches, microneedles, and molecularly imprinted polymeric systems. Each subsection describes an approach including key considerations in formulation development, design, and process parameters with schematics. An overview of commercially available conventional (adhesive) patches for long-acting drug delivery (longer than 24 h), the reservoir- and matrix-type systems under preclinical evaluation, as well as the advanced transdermal formulations, such as the core-shell, nanoformulations-incorporated and stimuli-responsive microneedles, and 3D-printed and molecularly imprinted polymers that are in development, is also provided. Finally, we elaborated on translational aspects, challenges in patch formulation development, and future directions for the clinical advancement of new long-acting transdermal products.

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Racism shapes the distribution of the social determinants of health (SDoH) along racial lines. Racism determines the environments in which people live, the quality of housing, and access to healthcare. Extensive research shows racism in its various forms negatively impacts health status, yet few studies and interventions seriously interrogate the role of racism in impacting health. The C2DREAM framework illuminates how exposure to racism, in multiple forms, connects to cardiovascular disease, hypertension, and obesity. The goal of the C2DREAM framework is to guide researchers to critically think about and measure the role of racism across its many levels of influence to better elucidate the ways it contributes to persistent health inequities. The conceptual framework highlights the interconnectedness between forms of racism, SDoH, and the lifecourse to provide a greater context to individual health outcomes. Utilizing this framework and critically contending with the effects of racism in its multiple and cumulative forms will lead to better research and interventions.

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Condylar resorption is an aggressive and disability form of temporomandibular joint (TMJ) degenerative disease, usually non-respondent to conservative or minimally invasive therapies and often leading to surgical intervention and prostheses implantation. This condition is also one of the most dreaded postoperative complications of orthognathic surgery, with severe cartilage erosion and loss of subchondral bone volume and mineral density, associated with a painful or not inflammatory processes. Because regenerative medicine has emerged as an alternative for orthopedic cases with advanced degenerative joint disease, we conducted a phase I/IIa clinical trial (U1111-1194-6997) to evaluate the safety and efficacy of autologous nasal septal chondroprogenitor cells. Ten participants underwent biopsy of the nasal septum cartilage during their orthognathic surgery. The harvested cells were cultured in vitro and analyzed for viability, presence of phenotype markers for mesenchymal stem and/or chondroprogenitor cells, and the potential to differentiate into chondrocytes, adipocytes, and osteoblasts. After the intra-articular injection of the cell therapy, clinical follow-up was performed using the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and computed tomography (CT) images. No serious adverse events related to the cell therapy injection were observed during the 12-month follow-up period. It was found that autologous chondroprogenitors reduced arthralgia, promoted stabilization of mandibular function and condylar volume, and regeneration of condylar tissues. This study demonstrates that chondroprogenitor cells from the nasal septum may be a promise strategy for the treatment of temporomandibular degenerative joint disease that do not respond to other conservative therapies.

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Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise.

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When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients.

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Purpose: This study aimed to introduce a novel [18F]AlF-labeled ODAP-Urea-based Prostate-specific membrane antigen (PSMA) probe, named [18F]AlF-PSMA-137, which was derived from the successful modification of glutamate-like functional group. The preclinically physical and biological characteristics of the probe were analyzed. Polit clinical PET/CT translation was performed to analyze its feasibility in clinical diagnosis of prostate cancer. Methods: [18F]AlF-PSMA-137 was maturely labeled with the [18F]AlF2+ labeling technique. It was analyzed by radio-HPLC for radiochemical purity and stability analysis in vitro and in vivo. The PSMA specificity was investigated in PSMA-positive (LNCaP) and PSMA-negative (PC3) cells, and the binding affinity was evaluated in LNCaP cells. Micro-PET/CT imaging was performed in mice bearing LNCaP or PC3 tumors. Thirteen patients with newly diagnosed prostate cancer were included for [18F]AlF-PSMA-137 PET/CT imaging. Physiologic biodistribution and tumor burden were semi-quantitatively evaluated and the radiation dosimetry of [18F]AlF-PSMA-137 was estimated. Results: The radiochemical yield of [18F]AlF-PSMA-137 was 54.2 ± 10.7% (n = 16) with the radiochemical purity over 99% and the specific activity of 26.36 ± 7.33 GBq/µmol. The binding affinity to PSMA was 2.11 ± 0.63 nM. [18F]AlF-PSMA-137 showed high cell/tumor uptake which can be specifically blocked by PSMA inhibitor. According to the biodistribution in patients, [18F]AlF-PSMA-137 was mainly accumulated in kidneys, lacrimal glands, parotid glands, submandibular glands and liver which was similar to the extensive Glu-Ureas based probes. A total of 81 lesions were detected in PET/CT imaging and over 91% of lesions increased between 1 h p.i. (SUVmean: 10.98 ± 18.12) and 2 h p.i. (SUVmean: 14.25 ± 21.28) (p < 0.001). Additionally, the probe showed intensive accumulation in lesions which provided excellent imaging contrast with the high tumor-to-muscle ratio of 15.57 ± 27.21 at 1 h p.i. and 25.42 ± 36.60 at 2 h p.i. (p < 0.001), respectively. The effective dose of [18F]AlF-PSMA-137 was estimated as 0.0119 ± 0.0009 mSv/MBq. Conclusion: An ODAP-Urea-based PSMA probe [18F]AlF-PSMA-137 was successfully prepared with high specificity and binding affinity to PSMA. Micro-PET/CT imaging study demonstrated its feasibility for prostate cancer imaging. Pilot clinical study showed its potential for delay-imaging and prostate cancer detection.

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The Mountain West Clinical Translational Research - Infrastructure Network (MW CTR-IN), established in 2013, is a research network of 13 university partners located among seven Institutional Development Award (IDeA) states targeting health disparities. This is an enormous undertaking because of the size of the infrastructure network (encompassing a third of the US landmass and spanning four time zones in predominantly rural and underserved areas, with populations that have major health disparities issues). In this paper, we apply the barriers, strategies, and metrics to an adapted educational conceptual model by Fink (2013). Applying this model, we used four tailored approaches across this regional infrastructure network to: (1) assess individual faculty specific needs, (2) reach out and engage with faculty, (3) provide customized services to meet the situational needs of faculty, and (4) utilize a "closed communication feedback loop" between Professional Development (PD) core and MW CTR-IN faculty within the context of their home institutional environment. Summary statement results from participating faculty show that these approaches were positive. Grounded in best educational practice approaches, we have an opportunity to refine and build from this sound foundation with implications for future use in other CTR-IN networks and institutions in the IDeA states.

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Retrospective case studies of initiatives supported by the National Institutes of Health's Clinical and Translational Science Award (CTSA) hubs can be used to identify facilitators and barriers of translational science. This case study investigates how a CTSA Expanded Access program adapted to changing FDA guidance issued in 2020 to support clinicians' treatment of COVID-19 patients in Michigan. We studied how this program changed throughout the pandemic to support physicians' requests for remdesivir, convalescent plasma, and other uses of unapproved drugs and novel medical devices. A protocol for retrospective translational science case studies of health interventions developed by CTSA evaluators was used for this case study. Data collection methods included seven interviews and a review of institutional data, peer-reviewed publications, news stories, and other public records. The barriers identified include evolving guidance, misalignment of organizational operations, and the complexity of the research infrastructure. The facilitators of translation include collaboration between research and care teams, increasing engagement with a broad network of supporters, and ongoing professional development for research staff. The findings of this case study can be used to inform future investigations of the principles underlying the translational process.

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This report presents an overview of how machine learning is rapidly advancing clinical translational imaging in ways that will aid in the early detection, prediction, and treatment of diseases that threaten brain health. Towards this goal, we aresharing the information presented at a symposium, "Neuroimaging Indicators of Brain Structure and Function - Closing the Gap Between Research and Clinical Application", co-hosted by the McCance Center for Brain Health at Mass General Hospital and the MIT HST Neuroimaging Training Program on February 12, 2021. The symposium focused on the potential for machine learning approaches, applied to increasingly large-scale neuroimaging datasets, to transform healthcare delivery and change the trajectory of brain health by addressing brain care earlier in the lifespan. While not exhaustive, this overview uniquely addresses many of the technical challenges from image formation, to analysis and visualization, to synthesis and incorporation into the clinical workflow. Some of the ethical challenges inherent to this work are also explored, as are some of the regulatory requirements for implementation. We seek to educate, motivate, and inspire graduate students, postdoctoral fellows, and early career investigators to contribute to a future where neuroimaging meaningfully contributes to the maintenance of brain health.

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PURPOSE: Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N-acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness. METHODS: Male and female Disc1 svΔ2 rats and age-matched, sex-matched Sprague-Dawley wild-type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region-specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 svΔ2 rats exposed to chronic early-life stress to test how gene-environment interactions might alter effectiveness of NAC therapy. RESULTS: The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early-life, sex-specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 svΔ2 rats. Addition of chronic early-life stress reduced the ability of NAC to restore microstructural deficits. CONCLUSION: These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.

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PURPOSE: In this study, a novel aluminium-[18F]fluoride (Al18F)-labelled 1,4,7­triazacyclononane-N,N',N″-triacetic acid (NOTA)-conjugated fibroblast activation protein inhibitor (FAPI) probe, named Al18F-NOTA-FAPI, was developed for fibroblast activation protein (FAP)-targeted tumour imaging; it could deliver hundreds of millicuries of radioactivity using automated synthesis. The tumour detection efficacy of Al18F-NOTA-FAPI was further validated in both preclinical and clinical translational studies. METHODS: The radiolabelling procedure of Al18F-NOTA-FAPI was optimized. Cell uptake and competitive binding assays were completed with the U87MG and A549 cell lines to evaluate the affinity and specificity of the Al18F-NOTA-FAPI probe. The biodistribution, pharmacokinetics, radiation dosimetry and tumour imaging efficacy of the Al18F-NOTA-FAPI probe were researched in healthy Kunming (KM) and/or U87MG model mice. After the approval of the ethical committee, the Al18F-NOTA-FAPI probe was translated into the clinic for PET/CT imaging of the first 10 cancer patients. RESULTS: The radiolabelling yield of Al18F-NOTA-FAPI was 33.8 ± 3.2% using manual synthesis (n = 10), with a radiochemical purity over 99% and the specific activity of 9.3-55.5 MBq/nmol. The whole body effective dose of Al18F-NOTA-FAPI was estimated to be 1.24E - 02 mSv/MBq, which was lower than several other FAPI probes (68Ga-FAPI-04, 68Ga-FAPI-46 and 68Ga-FAPI-74). In U87MG tumour-bearing mice, Al18F-NOTA-FAPI showed good tumour detection efficacy based on the results of micro PET/CT imaging and biodistribution studies. In an organ biodistribution study of patients, Al18F-NOTA-FAPI showed a lower SUVmean than 2-[18F]-fluoro-2-deoxy-D-glucose (2-[18F]FDG) in most organs, especially in the liver (1.1 ± 0.2 vs. 2.0 ± 0.9), brain (0.1 ± 0.0 vs. 5.9 ± 1.3), and bone marrow (0.9 ± 0.1 vs. 1.7 ± 0.4). Meanwhile, Al18F-NOTA-FAPI did not show extensive bone uptake, and was able to detect more lesions than 2-[18F]FDG in the PET/CT imaging of several patients. CONCLUSION: The Al18F-NOTA-FAPI probe was successfully fabricated and applied in fibroblast activation protein-targeted tumour PET/CT imaging, which showed excellent imaging quality and tumour detection efficacy in U87MG tumour-bearing mice as well as in cancer patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000038080. Registered 09 September 2020. http://www.chictr.org.cn/showproj.aspx?proj=61192.

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INTRODUCTION: COVID-19 altered research in Clinical and Translational Science Award (CTSA) hubs in an unprecedented manner, leading to adjustments for COVID-19 research. METHODS: CTSA members volunteered to conduct a review on the impact of CTSA network on COVID-19 pandemic with the assistance from NIH survey team in October 2020. The survey questions included the involvement of CTSAs in decision-making concerning the prioritization of COVID-19 studies. Descriptive and statistical analyses were conducted to analyze the survey data. RESULTS: 60 of the 64 CTSAs completed the survey. Most CTSAs lacked preparedness but promptly responded to the pandemic. Early disruption of research triggered, enhanced CTSA engagement, creation of dedicated research areas and triage for prioritization of COVID-19 studies. CTSAs involvement in decision-making were 16.75 times more likely to create dedicated diagnostic laboratories (95% confidence interval [CI] = 2.17-129.39; P < 0.01). Likewise, institutions with internal funding were 3.88 times more likely to establish COVID-19 dedicated research (95% CI = 1.12-13.40; P < 0.05). CTSAs were instrumental in securing funds and facilitating establishment of laboratory/clinical spaces for COVID-19 research. Workflow was modified to support contracting and IRB review at most institutions with CTSAs. To mitigate chaos generated by competing clinical trials, central feasibility committees were often formed for orderly review/prioritization. CONCLUSIONS: The lessons learned from the COVID-19 pandemic emphasize the pivotal role of CTSAs in prioritizing studies and establishing the necessary research infrastructure, and the importance of prompt and flexible research leadership with decision-making capacity to manage future pandemics.

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INTRODUCTION: Advance Clinical and Translational Research (Advance-CTR) serves as a central hub to support and educate clinical and translational researchers in Rhode Island. Understanding barriers to clinical research in the state is the key to setting project aims and priorities. METHODS: We implemented a Group Concept Mapping exercise to characterize the views of researchers and administrators regarding how to increase the quality and quantity of clinical and translational research in their settings. Participants generated ideas in response to this prompt and rated each unique idea in terms of how important it was and feasible it seemed to them. RESULTS: Participants generated 78 unique ideas, from which 9 key themes emerged (e.g., Building connections between researchers). Items rated highest in perceived importance and feasibility included providing seed grants for pilot projects, connecting researchers with common interests and networking opportunities. Implications of results are discussed. CONCLUSIONS: The Group Concept Mapping exercise enabled our project leadership to better understand stakeholder-perceived priorities and to act on ideas and aims most relevant to researchers in the state. This method is well suited to translational research enterprises beyond Rhode Island when a participatory evaluation stance is desired.

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One of the challenges in 3D-bioprinting is the realization of complex, volumetrically defined structures, that are also anatomically accurate and relevant. Towards this end, in this study we report the development and validation of a carboxylated agarose (CA)-based bioink that is amenable to 3D printing of free-standing structures with high stiffness at physiological temperature using microextrusion printing without the need for a fugitive phase or post-processing or support material (FRESH). By blending CA with negligible amounts of native agarose (NA) a bioink formulation (CANA) which is suitable for printing with nozzles of varying internal diameters under ideal pneumatic pressure was developed. The ability of the CANA ink to exhibit reproducible sol-gel transition at physiological temperature of 37 °C was established through rigorous characterization of the thermal behavior, and rheological properties. Using a customized bioprinter equipped with temperature-controlled nozzle and print bed, high-aspect ratio objects possessing anatomically-relevant curvature and architecture have been printed with high print reproducibility and dimension fidelity. Objects printed with CANA bioink were found to be structurally stable over a wide temperature range of 4 °C to 37 °C, and exhibited robust layer-to-layer bonding and integration, with evenly stratified structures, and a porous interior that is conducive to fluid transport. This exceptional layer-to-layer fusion (bonding) afforded by the CANA bioink during the print obviated the need for post-processing to stabilize printed structures. As a result, this novel CANA bioink is capable of yielding large (5-10 mm tall) free-standing objects ranging from simple tall cylinders, hemispheres, bifurcated 'Y'-shaped and 'S'-shaped hollow tubes, and cylinders with compartments without the need for support and/or a fugitive phase. Studies with human nasal chondrocytes showed that the CANA bioink is amenable to the incorporation of high density of cells (30 million/mL) without impact on printability. Furthermore, printed cells showed high viability and underwent mitosis which is necessary for promoting remodeling processes. The ability to print complex structures with high cell densities, combined with excellent cell and tissue biocompatibility of CA bodes well for the exploitation of CANA bioinks as a versatile 3D-bioprinting platform for the clinical translation of regenerative paradigms.

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BACKGROUND: Most adults are not achieving recommended levels of physical activity (150 minutes/week, moderate-to-vigorous intensity). Inadequate activity levels are associated with numerous poor health outcomes, and clinical recommendations endorse physical activity in the front-line treatment of obesity, diabetes, dyslipidemia, and hypertension. A framework for physical activity prescription and referral has been developed, but has not been widely implemented. This may be due, in part, to the lack of feasible and effective physical activity intervention programs designed to coordinate with clinical care delivery. OBJECTIVE: This manuscript describes the protocol for a pilot randomized controlled trial (RCT) that tests the efficacy of a 13-week online intervention for increasing physical activity in adult primary care patients (aged 21-70 years) reporting inadequate activity levels. The feasibility of implementing specific components of a physical activity clinical referral program, including screening for low activity levels and reporting patient program success to referring physicians, will also be examined. Analyses will include participant perspectives on maintaining physical activity. METHODS: This pilot study includes a 3-month wait-listed control RCT (1:1 ratio within age strata 21-54 and 55-70 years). After the RCT primary end point at 3 months, wait-listed participants are offered the full intervention and all participants are followed to 6 months after starting the intervention program. Primary RCT outcomes include differences across randomized groups in average step count, moderate-to-vigorous physical activity, and sedentary behavior (minutes/day) derived from accelerometers. Maintenance of physical activity changes will be examined for all participants at 6 months after the intervention start. RESULTS: Recruitment took place between October 2018 and May 2019 (79 participants were randomized). Data collection was completed in February 2020. Primary data analyses are ongoing. CONCLUSIONS: The results of this study will inform the development of a clinical referral program for physical activity improvement that combines an online intervention with clinical screening for low activity levels, support for postintervention behavior maintenance, and feedback to the referring physician. TRIAL REGISTRATION: ClinicalTrials.gov NCT03695016; https://clinicaltrials.gov/ct2/show/NCT03695016. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18891.

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This meeting report summarizes a Consultants Meeting that was held at International Atomic Energy Agency headquarters in Vienna to provide an update on radionuclide imaging for neuroscience applications.

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BACKGROUND: Clinical trial articles often lack detailed descriptions of the methods used to randomize participants, conceal allocation, and blind subjects and investigators to group assignment. We describe our systematic approach to implement and measure blinding success in a double-blind phase 2 randomized controlled trial testing the efficacy of acupuncture for the treatment of vulvodynia. METHODS: Randomization stratified by vulvodynia subtype is managed by Research Electronic Data Capture software's randomization module adapted to achieve complete masking of group allocation. Subject and acupuncturist blinding assessments are conducted multiple times to identify possible correlates of unblinding. RESULTS: At present, 48 subjects have been randomized and completed the protocol resulting in 87 subject and 206 acupuncturist blinding assessments. DISCUSSION: Our approach to blinding and blinding assessment has the potential to improve our understanding of unblinding over time in the presence of possible clinical improvement.

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