COPOLYMER HYDROGELS AS FULLY IMPLANTABLE OPTICAL BIOSENSORS: INVESTIGATING DESIGN PARADIGMS TO ACHIEVE LONG-TERM PRECLINICAL FUNCTION

Many diagnostic tests for disease management and overall health monitoring provide only an instantaneous measurement of the patient’s state of health, leaving intermediate fluctuations in biochemistry levels undisclosed. Often, fluid samples are collected periodically and analyzed using ex vivo assays. Diabetes is a prime example of this enigma where knowledge of blood biochemistry fluctuation patterns in real time could allow patients to make more informed treatment and lifestyle decisions. In recent years, hydrogels have been investigated as fully implantable biosensors by functionalizing them with enzymes and long-lifetime phosphors. However, maintaining a proper balance between enzyme stability and substrate transport when implanted has prevented preclinical proof of concept using this enzyme/phosphor sensing platform. This work explores the effect of matrix chemistry on enzyme stability and substrate transport and demonstrates the first noninvasive glucose tracking in porcine models by measuring luminescence lifetime instead of intensity. The first aim of this work focuses on poly(HEMA-co-AAm) matrices, characterizing them as glucose sensors in vitro and in vivo. A copolymer hydrogel containing 75:25 HEMA:AAm responded to up to 167 mg/dL of glucose in vitro and tracked real-time porcine blood glucose levels two hours after implantation, the first-reported real-time glucose tracking measuring phosphorescence lifetime using a noninvasive interrogation method. The second aim of this work employs alternative monomers such as dimethylacrylamide, N-vinyl pyrrolidone, and a 3- [Tris(trimethylsiloxy)silyl]propyl methacrylate to investigate enzyme stability and optimize substrate transport. These studies revealed that gels containing dimethylacrylamide and N-vinyl pyrrolidone provide the most enzyme stability, preserving between 60 and 93% of the original apparent activity after one week of incubation, but matrix inhomogeneities from adding silicone monomers can decrease sensor dynamic range by 56%. Finally, hybrid inorganic-organic interpenetrating network hydrogels were developed to prevent silicone phase separation in the hydrogels. These materials increased oxygen transport by up to 256% in vitro compared to pHEMA-based oxygen sensors and responded to modulated inspired oxygen in porcine models over 72 days. Hybrid sensors made with tissue-integrating inverted colloidal crystal architectures revealed minimal fibrosis in vivo with loosely woven collagen surrounding the implants, demonstrating promise for these hybrid materials as long-term implantable biosensors

COPOLYMER HYDROGELS AS FULLY IMPLANTABLE OPTICAL BIOSENSORS: INVESTIGATING DESIGN PARADIGMS TO ACHIEVE LONG-TERM PRECLINICAL FUNCTION

Many diagnostic tests for disease management and overall health monitoring provide only an instantaneous measurement of the patient’s state of health, leaving intermediate fluctuations in biochemistry levels undisclosed. Often, fluid samples are collected periodically and analyzed using ex vivo assays. Diabetes is a prime example of this enigma where knowledge of blood biochemistry fluctuation patterns in real time could allow patients to make more informed treatment and lifestyle decisions. In recent years, hydrogels have been investigated as fully implantable biosensors by functionalizing them with enzymes and long-lifetime phosphors. However, maintaining a proper balance between enzyme stability and substrate transport when implanted has prevented preclinical proof of concept using this enzyme/phosphor sensing platform. This work explores the effect of matrix chemistry on enzyme stability and substrate transport and demonstrates the first noninvasive glucose tracking in porcine models by measuring luminescence lifetime instead of intensity. The first aim of this work focuses on poly(HEMA-co-AAm) matrices, characterizing them as glucose sensors in vitro and in vivo. A copolymer hydrogel containing 75:25 HEMA:AAm responded to up to 167 mg/dL of glucose in vitro and tracked real-time porcine blood glucose levels two hours after implantation, the first-reported real-time glucose tracking measuring phosphorescence lifetime using a noninvasive interrogation method. The second aim of this work employs alternative monomers such as dimethylacrylamide, N-vinyl pyrrolidone, and a 3- [Tris(trimethylsiloxy)silyl]propyl methacrylate to investigate enzyme stability and optimize substrate transport. These studies revealed that gels containing dimethylacrylamide and N-vinyl pyrrolidone provide the most enzyme stability, preserving between 60 and 93% of the original apparent activity after one week of incubation, but matrix inhomogeneities from adding silicone monomers can decrease sensor dynamic range by 56%. Finally, hybrid inorganic-organic interpenetrating network hydrogels were developed to prevent silicone phase separation in the hydrogels. These materials increased oxygen transport by up to 256% in vitro compared to pHEMA-based oxygen sensors and responded to modulated inspired oxygen in porcine models over 72 days. Hybrid sensors made with tissue-integrating inverted colloidal crystal architectures revealed minimal fibrosis in vivo with loosely woven collagen surrounding the implants, demonstrating promise for these hybrid materials as long-term implantable biosensors

Establishing a Core Outcome Measure for Fatigue in Patients on Hemodialysis: A Standardized Outcomes in Nephrology–Hemodialysis (SONG-HD) Consensus Workshop Report

Fatigue is one of the most highly prioritized outcomes for patients and clinicians, but remains infrequently and inconsistently reported across trials in hemodialysis. We convened an international Standardized Outcomes in Nephrology–Hemodialysis (SONG-HD) consensus workshop with stakeholders to discuss the development and implementation of a core outcome measure for fatigue. 15 patients/caregivers and 42 health professionals (clinicians, researchers, policy makers, and industry representatives) from 9 countries participated in breakout discussions. Transcripts were analyzed thematically. 4 themes for a core outcome measure emerged. Drawing attention to a distinct and all-encompassing symptom was explicitly recognizing fatigue as a multifaceted symptom unique to hemodialysis. Emphasizing the pervasive impact of fatigue on life participation justified the focus on how fatigue severely impaired the patient’s ability to do usual activities. Ensuring relevance and accuracy in measuring fatigue would facilitate shared decision making about treatment. Minimizing burden of administration meant avoiding the cognitive burden, additional time, and resources required to use the measure. A core outcome measure that is simple, is short, and includes a focus on the severity of the impact of fatigue on life participation may facilitate consistent and meaningful measurement of fatigue in all trials to inform decision making and care of patients receiving hemodialysis

\u3ci\u3eDrosophila\u3c/i\u3e Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu