A Nanotherapeutic Device for Effective Non-Surgical Female Sterilization

The only non-surgical permanent birth control option currently available for women is a hysteroscopically implanted nickel-titanium coil, which causes inflammation in the Fallopian tube and through it the tubes’ irreversible blockage with scar tissue. We propose a novel device that can be inserted in the same way, but is resorbable, and can be imaged by ultrasound. The new device is immobilized in the Fallopian tubes after the local removal of the epithelial layer to cause first local inflammation and physical blockage, then scar formation and, finally, permanent tube blockage in only thirty days, followed by the devices’ self-removal from the tube by safe and non-toxic decomposition and resorption. This approach offers all advantages of the currently available commercial device, but at significantly reduced risks, and no longer requires X-ray-based imaging for placement and efficacy testing; additionally, it is potentially reversible by tubal cannulation.

NIH-NICHD - Ulrike G.K. Wegst (PI)

Multifunctional Freeze-Cast Scaffolds for Peripheral Nerve Repair

An estimated 2 million (5%) of the annual 40.2 million trauma-related emergency room admissions in the US require treatment for peripheral nerve injuries (PNI). These injuries occur in upper and lower extremities as well as in facial nerves, and frequently result in permanent disabilities such as sensory deficit, paralysis, and painful neuropathies. Although peripheral nerves possess the inherent ability to regenerate, nerve transections require surgical intervention to optimize functional recovery. While small gaps (≤5 mm) may be directly coapted, larger gaps (>5 mm) require interposition grafting with nerve auto- or allografts or conduits to provide tension free mechanical support, axon guidance, and protection from fibrous tissue ingrowth. Conduits avoid the substantial disadvantages of autografts such as a second surgical site, donor site morbidity, limited availability, and high treatment cost, however, current FDA approved devices are limited to use in defects ≤30 mm. Cadaveric nerve allografts are used only for defects ≤70 mm due to the limited regenerative capacity of neurons through such grafts. As a result, autografts remain the gold standard. However, even when direct repair or autografts are used, outcomes remain suboptimal with only 50% of patients with mixed nerve injuries regaining meaningful motor and sensory function, and less than 15% regaining full functionality. The purpose of the proposed project is to design, manufacture, and assess a novel biomaterial scaffold for peripheral nerve repair with highly-aligned, continuous porosity that emulates key structural and mechanical functions of the endoneurium; it further offers several options to incorporate biochemical cues aiding speed and quality of regeneration. Our preliminary results address several limitations of clinically available bioengineered neural conduits. We can reproducibly manufacture i) long scaffolds (>70 mm) with an endoneurium-like core structure ii) that are selectively coated and/or functionalized with bioactive polymers. Key to the proposed approach are the hypotheses that: i) an endoneurium-like porous core will increase the speed of axonal alignment and extension and quality of functional (sensory and motor) regeneration when compared to an autograft, and that iii) the proposed multifunctional scaffold will match or exceed the in vivo performance of autografts and enable the bridging and repair of increasingly long gaps. We address these hypotheses in an iterative process, in the following interrelated aims. AIM 1: Tailor structural and mechanical properties of the device that promotes and directs neurite growth and limits intrusion of scar tissue. Select the most promising for AIM 2: Evaluate biocompatibility and efficacy in a rodent sciatic nerve model.

Synergy-Dartmouth - Ulrike G.K. Wegst (PI), Michael K. Matthew, (Co-PI, Surgery/Plastic Surgery)

Collaborative Research: Modeling-Based Design of Freeze-Cast Hybrid Materials

The freeze-casting process is one with which bulk materials and entire components of several cubic centimeters in size can be manufactured with ease. The process is based on the solidification of water-based solutions or slurries (suspensions). To freeze-cast a scaffold, a solution or slurry is poured into a mold and then directionally solidified. During freezing, the water solidifies in the form of pure ice crystals, and the polymer that was dissolved and the particles that were suspended in this liquid carrier are concentrated between them. Once frozen, the sample is freeze-dried to sublime the ice-phase and reveal the material scaffold; its architecture is the negative of the ice crystals which templated it. The cell wall material structure is the result of a self-assembly process. Freeze casting or "ice templating" is a relatively inexpensive procedure and provides a means to mimic complex, efficient natural materials with hierarchical designs over several length-scales. This award supports research to build models, basic design principles and tools that will enable a systematic approach for the design and manufacture of freeze-cast hybrid materials with enhanced performance. These new materials will be of benefit to both individuals and the general public at large through applications that range from energy generation and storage to tissue repair and regeneration.

This research program focuses on the fundamental science and modeling-driven design of freeze-cast hybrid materials. An interdisciplinary team with expertise in modeling, experiment and characterization will address current knowledge gaps and analyze the formation and evolution of the ice phase and ice-templated material architectures generated by the freeze casting process in an attempt to uncover basic physicochemical principles and determine fundamental processing-structure-property correlations. The three research goals are to (1) determine the underlying fundamental materials science and establish a realistic model for ice-crystal nucleation and growth on a well-defined substrate (graphene) during freeze casting; (2) uncover processing-structure-property correlations by combining multiscale computational modeling with experimental approaches; and (3) develop predictive models to identify the most promising processing-additive combinations in order to custom-design and optimize structure formation and performance in the model material system.

NSF-CMMI - Ulrike G.K. Wegst (PI), Jifeng Liu (Co-PI)