Thermal stabilization of diverse biologics using reversible hydrogels.

Improving the thermal stability of biologics, including vaccines, is critical to reduce the economic costs and health risks associated with the cold chain. Here, we designed a versatile, safe, and easy-to-use reversible PEG-based hydrogel platform formed via dynamic covalent boronic ester cross-linking for the encapsulation, stabilization, and on-demand release of biologics. Using these reversible hydrogels, we thermally stabilized a wide range of biologics up to 65°C, including model enzymes, heat-sensitive clinical diagnostic enzymes (DNA gyrase and topoisomerase I), protein-based vaccines (H5N1 hemagglutinin), and whole viruses (adenovirus type 5). Our data support a generalized protection mechanism for the thermal stabilization of diverse biologics using direct encapsulation in reversible hydrogels. Furthermore, preliminary toxicology data suggest that the components of our hydrogel are safe for in vivo use. Our reversible hydrogel platform offers a simple material solution to mitigate the costs and risks associated with reliance on a continuous cold chain for biologic transport and storage.

Stress Relaxation and Composition of Hydrazone-Crosslinked Hybrid Biopolymer-Synthetic Hydrogels Determine Spreading and Secretory Properties of MSCs.

The extracellular matrix plays a critical role in mechanosensing and thereby influences the secretory properties of bone-marrow-derived mesenchymal stem/stromal cells (MSCs). As a result, interest has grown in the development of biomaterials with tunable properties for the expansion and delivery of MSCs that are used in cell-based therapies. Herein, stress-relaxing hydrogels are synthesized as hybrid networks containing both biopolymer and synthetic macromer components. Hyaluronic acid is functionalized with either aldehyde or hydrazide groups to form covalent adaptable hydrazone networks, which are stabilized by poly(ethylene glycol) functionalized with bicyclononyne and heterobifunctional small molecule crosslinkers containing azide and benzaldehyde moieties. Tuning the composition of these gels allows for controlled variation in the characteristic timescale for stress relaxation and the amount of stress relaxed. Over this compositional space, MSCs are observed to spread in formulations with higher degrees of adaptability, with aspect ratios of 1.60 ± 0.18, and YAP nuclear:cytoplasm ratios of 6.5 ± 1.3. Finally, a maximum MSC pericellular protein thickness of 1.45 ± 0.38 µm occurred in highly stress-relaxing gels, compared to 1.05 ± 0.25 µm in non-adaptable controls. Collectively, this study contributes a new understanding of the role of compositionally defined stress relaxation on MSCs mechanosensing and secretion.

The utility of magnetic resonance imaging results in physician decision-making before initial lumbar spinal injection.

BACKGROUND CONTEXT: The need for advanced imaging before spinal intervention is an area of ongoing debate. Many studies have demonstrated the accuracy of magnetic resonance imaging (MRI) results in evaluating structural pathology in the lumbar spine, but few have addressed how frequently MRI findings change clinical management. A randomized controlled trial showed that viewing MRI results did not impact outcomes in patients with radiculopathy undergoing epidural steroid injection (ESI). The results suggested ESIs that correlated with both imaging and clinical findings experienced slightly more benefit than the blinded cohort, although statistically insignificantly. PURPOSE: Three related studies were conducted to (1) increase understanding of the opinions of interventional spine physicians regarding the utility of viewing imaging before injection and (2) evaluate the impact of viewing MRI results on injection planning (retrospective and prospective analyses). STUDY DESIGN: Survey, prospective, and retrospective analysis. PATIENT SAMPLE: Patients presenting to a university-based spine center for initial evaluation of back or leg pain who were candidates for spinal intervention. OUTCOME MEASURES: Self-reported measures from a clinical practice questionnaire distributed to interventional spine physicians to determine rates and rationale for utilization of MRI before spine injection, physiologic measures including MRI results, functional measures including physician decision-making regarding type and location of injection performed. METHODS: This study was funded by the University of Colorado Health and Welfare Trust. A survey was sent to interventional spine physicians to assess their utilization of MRI results before spine procedures. A retrospective analysis of patients who were candidates for ESI was conducted to evaluate how initial injection plan compared with the postviewing of MRI results on injection performed. In a prospective analysis, injection plans pre- and post-MRI were compared among patients presenting for initial evaluation of low back or leg pain. RESULTS: Survey responses showed that specialists order MRI studies to correlate with physical exam (91%) and to detect the presence of synovial cysts (68%), whereas tumor/infection (93%) was most likely to cause a change in their approach. In the retrospective review, the physician's planned approach before viewing the MRI was concordant with the actual procedure 49% of the time. A different type of procedure was performed in 15% of planned injections. In such cases, the initial treatment plan was altered (ie, same procedure at a different or additional level or side) in 35% of planned injections. In the prospective data collection, 43% of injections were different from the initial physician decision. The most common reasons for altering the injection was different level affected (36%), facet pathology (22%), and different nerve root affected (16%). CONCLUSIONS: In clinical practice, MRI before injection frequently changes management decisions in the planning and delivery of lumbar spine injections.

Clinical Course of Motor Deficits from Lumbosacral Radiculopathy Due to Disk Herniation.

BACKGROUND: The clinical course of motor deficits from lumbosacral radiculopathy appears to improve with or without surgery. Strength measurements have been confined to manual muscle testing (MMT) and have not been extensively followed and quantified in prior studies. OBJECTIVE: To determine if motor weakness and patient-reported outcomes related to lumbosacral radiculopathy improve without surgical intervention over the course of 12 months. DESIGN: Prospective observational cohort. SETTING: Outpatient academic spine practice. PARTICIPANTS: Adults with acute radicular weakness due to disk herniation. METHODS: Forty patients with radiculopathy and strength deficit were followed over a 12-month period. Objective strength and performance tests as well as survey-based measurements were collected at baseline and then every 3 months. Patients underwent comprehensive pain management and rehabilitation and/or surgical approaches as determined in coordination with the treating specialist. This study was approved by the institutional review board of Colorado. MAIN OUTCOME MEASUREMENTS: Testing of strength was through MMT, handheld dynamometer, and performance-based testing. Furthermore, visual analog scale, modified Oswestry Disability Index, and 36-Item Short Form Health Survey (SF-36) were used to measure pain and disability outcomes. RESULTS: Of the 40 patients, 33 (82.5%) did not have surgery; 7 (17.5%) had surgery. Twenty-four of the 33 patients (60%) did not undergo surgery and were followed for 12 months (Comprehensive Pain Management and Rehabilitation, Complete [CPM&R-C]), and 9 (22%) did not have surgery and lacked at least one follow-up evaluation (Comprehensive Pain Management and Rehabilitation, Incomplete [CPM&R-I]). No statistically significant differences were found on baseline measures of strength deficits and SF-36 domains between the CPM&R-C, Surgery, and CPM&R-I groups. Pain and disability scores in the Surgery group were significantly higher than in the CPM&R-C at baseline. There were statistically significant improvements in all areas of strength, pain, and function when comparing measurements at the 12-month follow-up to baseline in the CPM&R-C group. CONCLUSIONS: Individuals with motor deficits due to lumbosacral radiculopathy improve over time regardless of treatment choice. Most did not choose surgery, and almost all of these patients regained full strength at 1 year. Strength recovery typically occurred in the first 3 months, but there was ongoing recovery over the course of a year. LEVEL OF EVIDENCE: II.