2013-2014 Research Highlights

Year 6 research efforts demonstrate the maturation and refocusing of projects begun in Years 3-5 with greater engagement by clinicians and industry collaborators to focus opportunities for translation. In particular, the development, processing and testing of novel degradable alloy systems has emerged as an area of strategic interest among ERC-RMB member companies. The underlying premise is that ERC-RMB sustainability is intimately tied to the intellectual strength of the team’s basic research, translational opportunities for our technologies and the commercial interest developed around this potential, as well as the educational impacts associated with next generation, diverse workforce quality and development.

Integrated Systems:

Craniofacial and Orthopedic Applications – ERC RMB researchers developed novel fixation plate and screw designs optimized for degradable metals and theoretically tested using finite element analysis (FEA). Optimized designs were manufactured for subsequent in vivo testing. These novel fixation plates and screws were evaluated using a semi-load bearing rabbit ulna fracture model. Device designs and material composition will be compared (novel design versus traditional design, and novel ERC alloy versus commercially available alloy). Evaluations included pull-out strength testing, x-ray and microCT analysis, and histology to measure fixation strength, material degradation behavior, tissue integration, fracture healing, and bone growth.

Cardiovascular and Thoracic Devices – ERC-RMB investigated fast-degrading stent designs in conjunction with the development of high strength ERC-RMB Mg-based alloy systems. Novel drug-eluting/non-thrombogenic elastomer coatings for degradable Mg-based alloys were developed and tested.

Sensor Integration – ERC-RMB investigators characterized in vivo corrosion study (Dr. Dong) on Mg alloys from NCAT (Dr. Yun), Pittsburgh (Dr. Kumta) and UC (Dr. Shanov) by monitoring H₂ through mouse skin with H₂ sensor, determining surface corrosion products on explanted samples using X-ray photoelectron microscopy, and measuring Mg ion distribution in mouse     organs and tissue surrounding implant using inductively coupled plasma mass spectrometry.         Sensors investigators also modified a spectrophotometric assay to use a plate reader to measure Mg in cell culture and corrosion studies.

Enabling Technologies and Cross-cutting Activities:

Novel Material Processing –Extrusion and thermal treatment of novel alloys at NCAT were expanded to establish a micro foundry for novel ERC-RMB alloys

Biocompatibility – Advanced basic research to identify the molecular mechanisms for improved bone and wound healing from Mg-based alloys.

Emerging Regulatory Science Focus (ASTM/ISO) – Participation with ATSM work group was implemented to create new international standards for safety testing of novel degradable metal implants.

Fundamental Science:

Corrosion Science – An ex vivo porcine artery model was developed to establish in vitro – in vivo correlation to identify flow and diffusion induced biodegradation behavior of magnesium based stents. Applied 3-D CT imaging technology to biodegradation analysis

Materials Science -The materials team developed series of Mg-based novel ERC alloys using strengthening functions of alloying elements, grain refinement ability of alloying elements and understanding the functions of alloying elements in corrosion. Improved heat treatment to prepare single phase Mg-Zn-(Ca)-REs to enhance mechanical and degradation properties as well as extrusion and wire drawing helped to manipulate microstructures resulting in understanding the property- structure relationships for the ERC- RMB Mg system

In vivo studies maturation:

TMJ Screw: Several different designs of magnesium bone screws were tested in vitro and in-vivo to assess the ease of implantation and probability of failure. ERC-RMB screws degraded at a clinically-relevant rate or slower than necessary. Based on the total number of in vitro and in-vivo tests conducted, the results showed that only 5 out of 56 third generation screws failed compared to 7 out of 23 first generation screws and 2 out of 5 second generation screws. A patent application was submitted based on the third generation TMJ screw design in February 2014.

ACL Screw: In vivo ACL reconstruction was performed using the 2nd generation Mg-based interference screws on 6 Spanish breed skeletally mature female goats with a 12 weeks recovery period. Compared to polymer-based interference screws, 2nd generation Mg-based interference screws resulted in improved joint stability and graft function at 12 weeks.

ACL-Ring: A pilot study (N = 2) was performed in skeletally mature, female Spanish goats to investigate the advantages of using an Mg-alloy repair ring with a sheet of extracellular matrix (ECM) ECM and hydrogel for ACL healing. Preliminary results of the healing study indicate that healthy tissue had bridged the gap between injured ends of the ACL as the Mg ring underwent degradation.

Bone Fracture Plate/Screw: A bilateral defect model in New Zealand White rabbits was used in which one complete ulnar osteotomy (0.5 - 1 mm thick) was created in both the right and left forearms (n = 6). One plate and four screws were used to stabilize each osteotomy. Forearms were left un-casted for eight and 16 weeks. Results showed an increase in flexure load for both Mg and ERC-P-04 samples when compared to healthy controls (though not significant), demonstrating no difference in forearm quality after healing and new bone growth. High resolution microCT demonstrated fracture healing, new bone formation, and device degradation. Partial bone overgrowth was observed at eight weeks, with complete bone covering nearly all devices after 16 weeks.

AV-Fistula Stent: Generation III stents were extensively tested in the pig model. In the experiment, AVFs were created bilateral in the groin AVFS on one side and the control AVF on the contralateral side. Clinical end points of flow and diameter were measured. Mild neointimal hyperplasia (NH) was observed at stented segment. Heavy NH was observed in non-stented fistula. No necrosis was observed. New stent designs (Generation IV) and novel coatings technologies are being studied to reduce NH.

Nerve Repair: Incorporated microCT imaging of soft tissues to study nerve repair. Refined requirements needed to make long gap nerve repair with Mg wire possible. In a pig model of stroke, it was demonstrated that injecting Mg ions shortly after stroke initiation can improve tissue integrity at 24 hrs. after stroke (paper in preparation). Developing Mg ion releasing beads at NCAT and evaluating biocompatibility in vitro with a human neural cell line.

Combinatorial Approaches (Degradable metals and ECM) – Degradable metals with biological augmentation were evaluated in vivo to study mechanical performance and the restoration of functional tissue in large animals (Spanish goats). A combinatorial study is in preliminary stages to evaluate the use of degradable alloys in esophageal injury.

Publications / Patents / Key Meetings:

• The impact of ERC RMB’s science continues to be demonstrated through a strong publication record and presence at key symposia, including as invited/keynote speakers. Invention disclosures and patent applications are increasing.
• For the reporting period, 43 journal papers, 8 books/book chapters/trade journal and 11 peer-reviewed conference proceedings papers were published from ERC-supported projects, 28 (26 journal articles and 2 peer-reviewed proceedings) from the associated projects and 8 journal articles from the sponsored projects.
• ERC members attended 48 scientific conferences, conducted 5 workshops/short courses and gave 59 seminars/colloquia/invited talks. Many of invention disclosures and patents include researchers from the all core partner universities.

Technology Transfer and Commercialization (Innovation Ecosystem):

• During 2013-2014 reporting period, the ERC has produced 5 additional Disclosures, bringing the total to 29, including topics involved in all Engineering Platforms.
• During the reporting period ERC-RMB 6 provisional and 2 full patents were filed.
• Enhancing Opportunities for Industrial Engagement: Revisions to the Membership Agreement were successfully initiated
• SBIR/STTR/SECO grants (ongoing with NanoMag, OrthoKinetics Lab)
• On October 25, 2013, inCube Labs entered into an option to license agreement to explore the translational potential of ERC materials based technologies for orthopedic applications. This collaboration between inCube Labs and the ERC represents a key validation and critical step in moving ERC technology toward commercialization.
• AV Fistula Stent : Generation III stents attracted a product discovery team from a major medical company
• America Makes – ERC-RMB was awarded a grant (Through University of Pittsburgh) to investigate the use of additive manufacturing to create complex structures that feature advanced biocompatible, biodegradable alloys and coatings technologies developed by ERC-RMB to promote natural tissue growth and healing.