Composite Biosynthetic Graft for Repair of Long-Segment Tracheal Stenosis: A Pilot In Vivo and In Vitro Feasibility Study.

Pediatric patients who undergo surgery for long-segment congenital tracheal stenosis (LSCTS) have suboptimal outcomes and postsurgical complications. To address this, we propose a biosynthetic graft comprising (1) a porcine small intestinal submucosa extracellular matrix (SIS-ECM) patch for tracheal repair, and (2) a resorbable polymeric exostent for biomechanical support. The SIS-ECM patch was evaluated in vivo in an ovine trachea model over an 8 month period. Concurrently, the biosynthetic graft was evaluated in a benchtop lamb trachea model for biomechanical stability. In vivo results show that SIS-ECM performs better than bovine pericardium (control) by preventing granulation tissue/restenosis, restoring tracheal architecture, blood vessels, matrix components, pseudostratified columnar and stratified epithelium, ciliary structures, mucin production, and goblet cells. In vitro tests show that the biosynthetic graft can provide the desired axial and flexural stability, and biomechanical function approaching that of native trachea. These results encourage future studies to evaluate safety and efficacy, including biomechanics and collapse risk, biodegradation, and in vivo response enabling a stable long-term tracheal repair option for pediatric patients with LSCTS and other tracheal defects.

The ChorioAnchor: Design and Testing of a Novel Chorioamniotic Anchoring Device to Enable Percutaneous Fetoscopic Surgery.

INTRODUCTION: Percutaneous fetoscopic surgery is hampered by an increased risk of preterm prelabor rupture of membranes (PPROM). Recent surgical techniques have shown that suturing the chorioamniotic membranes following laparotomy and uterine exteriorization is associated with a lower risk of PPROM compared to percutaneous in utero surgery. This study presents the ChorioAnchor, a novel resorbable device that percutaneously anchors the chorioamniotic membranes to the uterine wall. METHODS: Human factors testing and peel tests were used to simulate the worst-case in-use loading conditions, establishing the device strength requirements. Tensile testing was used to measure the time-zero strength of the device. Porcine cadaver testing was used to examine ultrasound visibility and acute handling characteristics. Short-term host response was examined through an acute 7-day implantation study in a rabbit model. RESULTS: With a time-zero tensile strength of 47 N, the ChorioAnchor exceeded the established 4 N strength requirement. Both the ChorioAnchor and delivery device were seen to be clearly visible under ultrasound imaging. Short-term host response to the device was well within the range expected for this type of device. CONCLUSION: The ChorioAnchor meets its engineering requirements in the early stages of implantation. Future studies will examine the kinetics of degradation of the device in vitro and in vivo.

Improved Low-Glucose Predictive Alerts Based on Sustained Hypoglycemia: Model Development and Validation Study.

BACKGROUND: Predictive alerts for impending hypoglycemic events enable persons with type 1 diabetes to take preventive actions and avoid serious consequences. OBJECTIVE: This study aimed to develop a prediction model for hypoglycemic events with a low false alert rate, high sensitivity and specificity, and good generalizability to new patients and time periods. METHODS: Performance improvement by focusing on sustained hypoglycemic events, defined as glucose values less than 70 mg/dL for at least 15 minutes, was explored. Two different modeling approaches were considered: (1) a classification-based method to directly predict sustained hypoglycemic events, and (2) a regression-based prediction of glucose at multiple time points in the prediction horizon and subsequent inference of sustained hypoglycemia. To address the generalizability and robustness of the model, two different validation mechanisms were considered: (1) patient-based validation (model performance was evaluated on new patients), and (2) time-based validation (model performance was evaluated on new time periods). RESULTS: This study utilized data from 110 patients over 30-90 days comprising 1.6 million continuous glucose monitoring values under normal living conditions. The model accurately predicted sustained events with >97% sensitivity and specificity for both 30- and 60-minute prediction horizons. The false alert rate was kept to <25%. The results were consistent across patient- and time-based validation strategies. CONCLUSIONS: Providing alerts focused on sustained events instead of all hypoglycemic events reduces the false alert rate and improves sensitivity and specificity. It also results in models that have better generalizability to new patients and time periods.

Advancing pediatric medical device development via non-dilutive NIH SBIR/STTR grant funding.

INTRODUCTION: A shortage of medical devices designed for children persists due to the smaller pediatric population and market factors. Furthermore, pediatric device development is challenging due to the limited available funding sources. We describe our experience with pediatric device projects that successfully received federal grant support towards commercializing the devices that can serve as a guide for future innovators. METHODS: The developmental pathways of pediatric device projects at a tertiary-care children's hospital that received NIH SBIR/STTR funding between 2016-2019 were reviewed. The clinical problems, designs, specific aims, and development phase were delineated. RESULTS: Pediatric faculty successfully secured NIH SBIR/STTR funding for five pediatric devices via qualified small business concerns (SBC's). Three projects were initiated in the capstone engineering design programs and developed further at two affiliated engineering schools, while the other two projects were developed in the faculty members' labs. Four projects received funding via established SBC's, while one was awarded funding via a newly established SBC. CONCLUSION: NIH SBIR/STTR grants are an essential source of external non-dilutive funding for pediatric device innovation and especially for academic-initiated projects. This funding can provide needed early-stage support to facilitate commercialization. In addition, these grants can serve as achievable accomplishments for pediatric faculty portfolios toward academic promotion. Our experience shows that it is possible to build a robust innovation ecosystem comprised of academic faculty (clinical/engineering) collaborating with local device development companies while jointly implementing a product development strategy leveraging NIH SBIR/STTR funding for critical translational research phases of pediatric device development.

Feature-Based Machine Learning Model for Real-Time Hypoglycemia Prediction.

BACKGROUND: Hypoglycemia is a serious health concern in youth with type 1 diabetes (T1D). Real-time data from continuous glucose monitoring (CGM) can be used to predict hypoglycemic risk, allowing patients to take timely intervention measures. METHODS: A machine learning model is developed for probabilistic prediction of hypoglycemia (<70 mg/dL) in 30- and 60-minute time horizons based on CGM datasets obtained from 112 patients over a range of 90 days consisting of over 1.6 million CGM values under normal living conditions. A comprehensive set of features relevant for hypoglycemia are developed and a parsimonious subset with most influence on predicting hypoglycemic risk is identified. Model performance is evaluated both with and without contextual information on insulin and carbohydrate intake. RESULTS: The model predicted hypoglycemia with >91% sensitivity for 30- and 60-minute prediction horizons while maintaining specificity >90%. Inclusion of insulin and carbohydrate data yielded performance improvement for 60-minute but not for 30-minute predictions. Model performance was highest for nocturnal hypoglycemia (~95% sensitivity). Shortterm (less than one hour) and medium-term (one to four hours) features for good prediction performance are identified. CONCLUSIONS: Innovative feature identification facilitated high performance for hypoglycemia risk prediction in pediatric youth with T1D. Timely alerts of impending hypoglycemia may enable proactive measures to avoid severe hypoglycemia and achieve optimal glycemic control. The model will be deployed on a patient-facing smartphone application in an upcoming pilot study.

Pediatric medical device development by surgeons via capstone engineering design programs.

BACKGROUND: There is a need for pediatric medical devices that accommodate the unique physiology and anatomy of pediatric patients that is increasingly receiving more attention. However, there is limited literature on the programs within children's hospitals and academia that can support pediatric device development. We describe our experience with pediatric device design utilizing collaborations between a children's hospital and two engineering schools. METHODS: Utilizing the academic year as a timeline, unmet pediatric device needs were identified by surgical faculty and matched with an engineering mentor and a team of students within the Capstone Engineering Design programs at two universities. The final prototypes were showcased at the end of the academic year and if appropriate, provisional patent applications were filed. RESULTS: All twelve teams successfully developed device prototypes, and five teams obtained provisional patents. The prototypes that obtained provisional patents included a non-operative ureteral stent removal system, an evacuation device for small kidney stone fragments, a mechanical leech, an anchoring system of the chorio-amniotic membranes during fetal surgery, and a fetal oxygenation monitor during fetoscopic procedures. CONCLUSIONS: Capstone Engineering Design programs in partnership with surgical faculty at children's hospitals can play an effective role in the prototype development of novel pediatric medical devices. LEVELS OF EVIDENCE: N/A - No clinical subjects or human testing was performed.

Passive biomechanical properties of human cadaveric levator ani muscle at low strains.

The objective of this study was to measure and model the passive biomechanics of cadaveric levator ani muscle in the fiber direction at low strains with a moderately slow deformation rate. Nine levator ani samples, extracted from female cadavers aged 64 to 96 years, underwent preconditioning and uniaxial biomechanical analysis on a tensile testing apparatus after the original width, thickness, and length were measured. The load extension data and measured dimensions were used to calculate stress-strain curves for each sample. The resulting stress-strain curves up to 10% strain were fit to four different constitutive models to determine which model was most appropriate for the data. A power-law model with two parameters was found to fit the data most accurately. Constitutive parameters did not correlate significantly with age in this study; this may be because all of the cadavers were postmenopausal.

2pBAb5. Validation of three-dimensional strain tracking by volumetric ultrasound image correlation in a pubovisceral muscle model.

Little is understood about the biomechanical changes leading to pelvic floor disorders such as stress urinary incontinence. In order to measure regional biomechanical properties of the pelvic floor muscles in vivo, a three dimensional (3D) strain tracking technique employing correlation of volumetric ultrasound images has been implemented. In this technique, local 3D displacements are determined as a function of applied stress and then converted to strain maps. To validate this approach, an in vitro model of the pubovisceral muscle, with a hemispherical indenter emulating the downward stress caused by intra-abdominal pressure, was constructed. Volumetric B-scan images were recorded as a function of indenter displacement while muscle strain was measured independently by a sonomicrometry system (Sonometrics). Local strains were computed by ultrasound image correlation and compared with sonomicrometry-measured strains to assess strain tracking accuracy. Image correlation by maximizing an exponential likelihood function was found more reliable than the Pearson correlation coefficient. Strain accuracy was dependent on sizes of the subvolumes used for image correlation, relative to characteristic speckle length scales of the images. Decorrelation of echo signals was mapped as a function of indenter displacement and local tissue orientation. Strain measurement accuracy was weakly related to local echo decorrelation.

Effect of length of the engineered tendon construct on its structure-function relationships in culture.

Constructs containing autogenous mesenchymal stem cells (MSCs) seeded in collagen gels have been used by our group to repair rabbit central patellar tendon defect injuries. Although these cell-gel composites exhibit improved repair biomechanics compared to natural healing, they can be difficult to handle at surgery and lack the necessary stiffness to resist peak in vivo forces early thereafter. MSCs are typically suspended in collagen gels around two posts in the base of a well in a specially designed silicone dish. The distance between posts is approximately the length of the tendon wound site. MSCs contract the gel around the posts prior to removal of the construct for implantation at surgery. We hypothesized that in vitro construct alignment and stiffness might be enhanced in the midregion of the longer construct where the end effects of the posts on the bulk material (St. Venant effects) could be minimized. Rabbit MSCs were seeded in purified bovine collagen gel at 0.04 M cells/mg collagen. The cell-gel mixture was pipetted into silicone dishes having two post-to-post lengths (short: 11 mm and long: 51 mm) but equivalent well widths and depths and post diameters. After 14 days of incubation, tensile stiffness and modulus of the constructs were measured using equivalent grip-to-grip lengths. Collagen fiber orientation index or OI (which measures angular dispersion of fibers) was quantified using small angle light scattering (SALS). Long constructs showed significantly lower angular dispersion vs. short constructs (OI of 41.24 degrees +/-1.57 degrees vs. 48.43 degrees +/-1.27 degrees , mean+/-SEM, p<0.001) with significantly higher linear modulus (0.064+/-0.009 MPa vs. 0.024+/-0.004 MPa, p=0.0022) and linear stiffness (0.031+/-0.005 MPa vs. 0.018+/-0.004 N/mm, mean+/-SEM, respectively, p=0.0404). We now plan to use principles of functional tissue engineering to determine if repairs containing central regions of longer MSC-collagen constructs improve defect repair biomechanics after implantation at surgery.

PelvicSim--a computational-experimental system for biomechanical evaluation of female pelvic floor organ disorders and associated minimally invasive interventions.

In this paper we describe the prototype of a new computational simulation system, PelvicSim. This system is being developed to simulate the in vivo biomechanics of the female pelvic floor organ system with the intent to provide clinical researchers, medical device designers with a virtual environment to understand the various biomechanical pathologies occurring in the pelvic floor. This information can then be used to develop new reconstructive surgical techniques, or design non surgical/surgical devices for the treatment of urinary incontinence and pelvic organ prolapse. In this paper, we provide the initial results from the development of the PelvicSim modules which combine in vivo sensing experiments, Ultrasound and MRI imaging datasets, and an inverse finite element modeling technology based on hyperviscoelastic constitutive modeling of the pelvic floor organs and tissues.

Meniscal material properties are minimally affected by matrix stabilization using glutaraldehyde and glycation with ribose.

Knee meniscus replacement holds promise, but current allografts are susceptible to biodegradation. Matrix stabilization with glutaraldehyde, a crosslinking agent used clinically to fabricate cardiovascular bioprostheses, or with glycation, a process of crosslinking collagen with sugars such as ribose, is a potential means of rendering tissue resistant to such degradation. However, stabilization should not significantly alter meniscal material properties, which could disturb normal function in the knee. Our objective was to evaluate the effects of glutaraldehyde- and glycation-induced matrix stabilization on the material properties of porcine meniscus. Normal untreated meniscus specimens were tested in confined compression at one of three applied stresses (0.069, 0.208, 0.347 MPa), subjected to either a glutaraldehyde or glycation stabilization treatment, and then re-tested to measure changes in tissue aggregate modulus, permeability, and compressive strain at equilibrium. Changes in these properties significantly increased with glutaraldehyde concentration and exposure time to ribose. One glutaraldehyde and three glycation treatments did not alter aggregate modulus or compressive strain at equilibrium compared to controls (p > 0.10). However, all treatments increased permeability by at least 108% compared to controls (p < 0.001). This study reveals a dose-dependent relationship between meniscal material properties and certain stabilization conditions and identifies treatments that minimally affect these properties. Further research is necessary to determine whether these treatments prevent enzymatic degradation before and after surgical implantation in the knee.

Effects of matrix stabilization when using glutaraldehyde on the material properties of porcine meniscus.

Meniscus transplantation frequently is one of the only options available for treating symptomatic younger patients with tibiofemoral pain and early arthrosis after a prior meniscectomy. However, clinical results indicate that current meniscal allografts may undergo degenerative changes due to enzymatic degradation during the remodeling phase. The objective of this study was to evaluate the effects of glutaraldehyde-induced matrix stabilization on the material properties of porcine meniscus prior to surgical implantation. Protocols for fabricating heart-valve replacements were examined, followed by an exploration of the effects of reducing glutaraldehyde concentration and exposure time. Cylindrical meniscus specimens were tested in uniaxial confined compression under a 0.196 MPa compressive stress, and aggregate modulus (H(A)), permeability (k), and compressive strains at equilibrium (epsilon(eq)) were calculated from the creep response. Compared to controls, the mean values for H(A) and k increased, on average, by 213 and 709%, respectively, and epsilon(eq) decreased by 57% for all "heart-valve" treatments. Reducing tissue exposure time to glutaraldehyde had little effect, but decreasing glutaraldehyde concentration to 0.02% resulted in tissues with material properties no different from the untreated controls. We conclude that minimal concentrations of glutaraldehyde (less than 0.2%) should be used in future studies to preserve normal meniscus properties.