Rate Acceleration of Organocatalytic Ring-Opening Polymerization rough the Application of Bis- and Tris- ( io)Urea H- Bond Donors

Well-defined and functionalized polymers have a wide variety of applications in biomedical studies. Advancements in the fields of drug delivery, microelectronics, and medical imaging, among other applications, are predicated upon the development of methods for the synthesis of precision polymers. Organocatalytic ring-opening polymerization (ROP) of cyclic monomers is an effective route to the production of polymeric materials, namely polyesters and polycarbonates, whose biodegradable properties make them a viable option in biomedical research. Arguably, H-bond mediated catalysts are among the most selective catalysts for ROP, giving rise to highly functionalized polycarbonates, well-controlled polymerizations, and other custom tailored applications. With respect to drug delivery, such polymers can be used as transporters to carry cargo molecules to cells, release their cargo, and then degrade safely. These capabilities, along with many others, give polymers derived through organocatalytic ROP great potential in biomaterials applications. Despite the applicability of its products, there is a major problem associated with organocatalytic ROP, and this is the dearth of efficient methods for the synthesis of well-defined polymers. One highly-selective system for polymer synthesis employs an H-bond donating cocatalyst (typically a thiourea) and an H-bond accepting base. Despite their selectivity, these catalysts are inefficient, requiring both high quantities of the cocatalysts and long reaction periods. However, my development of systems for the ROP of cyclic ester monomers, namely δ-valerolactone and ε-caprolactone, involving various H-bond donating bis- and tris- (thio)urea cocatalysts has yielded significant reaction rate enhancement in comparison with that of the monomeric analogue. Polymerizations catalyzed by the tris-urea cocatalyst exhibited reaction rates up to 100 times those of ROPs employing the previously disclosed mono-thiourea. Despite this significant rate enhancement, these polymerizations retain the characteristics of ‘living’ polymerizations: low polydispersity, predictable molecular weight, and linear evolution of molecular weight with conversion. A mechanism for the rate acceleration with both bis- and tris- catalysts is proposed

Next generation near infrared (NIR) and shortwave infrared (SWIR) wearables for breast cancer imaging

Neoadjuvant chemotherapy (NAC) is a common breast cancer treatment that involves administering chemotherapy for 3-6 months prior to surgery. This treatment enables more breast-conserving surgeries and even allows for the omission of surgery in some cases. However, about 31% of patients receiving NAC do not respond to the treatment. Therefore, there is a need for real-time methods to predict treatment response and improve patient outcomes. Over the last two decades, diffuse optical imaging has been investigated as a potential solution to this problem. This noninvasive and inexpensive technology uses near or shortwave infrared (NIR or SWIR) light to illuminate tissue, and detects multiply-scattered photons. However, bulky instrumentation and complicated imaging procedures have limited the clinical adoption of this technology. Furthermore, measured biomarkers including oxy- and deoxy-hemoglobin (HbO2 and HHb, respectively), water, and lipid, have had mixed results in terms of prognostic capability. To address these limitations, a new wearable optical probe technology was developed and validated in this project, including a high-optode density NIR probe for monitoring hemodynamics and a first-generation SWIR probe for quantifying water and lipid. Measurements on tissue-mimicking channel flow phantoms confirmed the ability of the NIR probe to quantify absorption contrast in vitro, and a cuff occlusion measurement demonstrated sensitivity to HbO2 and HHb in vivo. Hemodynamic oscillations at the respiratory rate were also explored in healthy volunteers and breast cancer patients as a potential new biomarker. It was demonstrated that traditional and novel breathing-related hemodynamic metrics provide tumor contrast and can potentially track treatment response. A deep-learning algorithm was developed to extract water and lipid concentrations from multi-distance SWIR measurements. The SWIR probe was validated by comparing measured water and lipid concentrations against ground truth values in emulsion phantoms. This work represents a significant step toward the development of technologies for frequent breast cancer treatment monitoring in the clinic and potentially at home

High optode-density wearable diffuse optical probe for monitoring paced breathing hemodynamics in breast tissue

Significance: Diffuse optical imaging (DOI) provides in vivo quantification of tissue chromophores such as oxy- and deoxyhemoglobin ([Formula: see text] and HHb, respectively). These parameters have been shown to be useful for predicting neoadjuvant treatment response in breast cancer patients. However, most DOI devices designed for the breast are nonportable, making frequent longitudinal monitoring during treatment a challenge. Furthermore, hemodynamics related to the respiratory cycle are currently unexplored in the breast and may have prognostic value. Aim: To design, fabricate, and validate a high optode-density wearable continuous wave diffuse optical probe for the monitoring of breathing hemodynamics in breast tissue. Approach: The probe has a rigid-flex design with 16 dual-wavelength sources and 16 detectors. Performance was characterized on tissue-simulating phantoms, and validation was performed through flow phantom and cuff occlusion measurements. The breasts of [Formula: see text] healthy volunteers were measured while performing a breathing protocol. Results: The probe has 512 unique source–detector (S-D) pairs that span S-D separations of 10 to 54 mm. It exhibited good performance characteristics: [Formula: see text] drift of 0.34%/h, [Formula: see text] precision of 0.063%, and mean [Formula: see text] up to 41 mm S-D separation. Absorption contrast was detected in flow phantoms at depths exceeding 28 mm. A cuff occlusion measurement confirmed the ability of the probe to track expected hemodynamics in vivo. Breast measurements on healthy volunteers during paced breathing revealed median signal-to-motion artifact ratios ranging from 8.1 to 8.7 dB. Median [Formula: see text] and [Formula: see text] amplitudes ranged from 0.39 to [Formula: see text] and 0.08 to [Formula: see text] , respectively. Median oxygen saturations at the respiratory rate ranged from 82% to 87%. Conclusions: A wearable diffuse optical probe has been designed and fabricated for the measurement of breast tissue hemodynamics. This device is capable of quantifying breathing-related hemodynamics in healthy breast tissue

Poor performance of the rapid test for human brucellosis in health facilities in Kenya

Human brucellosis is considered to be an important but typically under-diagnosed cause of febrile illness in many low and middle-income countries. In Kenya, and throughout East Africa, laboratory diagnosis for the disease is based primarily on the febrile antigen Brucella agglutination test (FBAT), yet few studies of the diagnostic accuracy of this test exist. Assessment of the performance of the FBAT is essential for its appropriate clinical use, as well as for evaluating surveillance data reported by public health systems. To assess FBAT performance, we collected sera from people with symptoms compatible with brucellosis attending two health facilities in Busia County, Kenya. Sera were tested using the FBAT and results compared with those from the Rose Bengal Test (RBT), an assay with well-known performance characteristics. Positives on either test were confirmed using the classical serum agglutination test (SAT)-Coombs test combination and a rapid IgM/IgG lateral flow immunochromatography assay (LFA). A questionnaire focussing on known risk factors for exposure to Brucella spp. was also conducted, and relationships with FBAT positivity examined using logistic regression. Out of 825 recruited individuals, 162 (19.6%) were classified as positive using the FBAT. In contrast, only eight (1.0%) were positive using the RBT. Of the 162 FBAT positives, one (0.62%) had an atypical agglutination in SAT and three (1.9%) showed low Coombs titres. Out of 148 FBAT positive individuals tested using the LFA, five (3.4%) were IgM positive and none were IgG positive. Poor or no correlation was observed between FBAT results and most established risk factors for Brucella infection. We observed substantial disagreement between the FBAT and a number of well-known serological tests, with the majority of reactive FBAT results appearing to be false positives. Poor FBAT specificity, combined with a lack of confirmatory testing, strongly suggests overdiagnosis of brucellosis is common in this low prevalence setting. This is expected to have important economic impacts on affected patients subjected to the long and likely unnecessary courses of multiple antibiotics required for treatment of the disease

Rate Accelerated Organocatalytic Ring-Opening Polymerization of l-Lactide via the Application of a Bis(thiourea) H-bond Donating Cocatalyst

A cocatalyst system consisting of an alkylamine base and a bis(thiourea) featuring a linear alkane tether is shown to dramatically increase the rate of ring-opening polymerization (ROP) of l-lactide versus previously disclosed monothiourea H-bond donors. Rate acceleration occurs regardless of the identity of the alkylamine cocatalyst, and the ROP remains controlled yielding poly(lactide) with narrow molecular weight distributions, predictable molecular weights and high selectivity for monomer. This H-bond mediated ROP of l-lactide constitutes a rare, clear example of rate acceleration with bis(thiourea) H-bond donors versus monothioureas, and the bis(thiourea) is shown to remain highly active for ROP at fractional percent catalyst loadings. Activation at a single monomer ester by both thiourea moieties is implicated as the source of rate acceleration

Bis- and Tris-Urea H‑Bond Donors for Ring-Opening Polymerization: Unprecedented Activity and Control from an Organocatalyst

A new class of H-bond donating ureas was developed for the ring-opening polymerization (ROP) of lactone monomers, and they exhibit dramatic rate acceleration versus previous H-bond mediated polymerization catalysts. The most active of these new catalysts, a tris-urea H-bond donor, is among the most active organocatalysts known for ROP, yet it retains the high selectivity of H-bond mediated organocatalysts. The urea cocatalyst, along with an H-bond accepting base, exhibits the characteristics of a “living” ROP, is highly active, in one case, accelerating a reaction from days to minutes, and remains active at low catalyst loadings. The rate acceleration exhibited by this H-bond donor occurs for all base cocatalysts examined. A mechanism of action is proposed, and the new catalysts are shown to accelerate small molecule transesterifications versus currently known monothiourea catalysts. It is no longer necessary to choose between a highly active or highly selective organocatalyst for ROP