Technologies 2018

Neuroprotective Monoclonal Antibodies

Artificial Placenta

Fused Deposition Modelling

Treatment of Central Nervous System Injuries Through Targeted Reduction of Neuroinflammation

A suite of neuroprotective monoclonal antibodies targeting CD11d, which has a role in inflammation

Background

Traumatic injuries to the brain and spinal cord are a leading cause of death among young people. Patients who are fortunate to survive the initial injury often deal with lifelong neurological impairment. With incident rates on the rise, traumatic brain injury (TBI) and spinal cord (SCI) are poised to become a major contributor to the global epidemiological and economic burden among traumatic injuries.

The extent of the tissue damage suffered by TBI and SCI patients is determined not only by the primary injury sustained through mechanical forces applied to the tissues but through a secondary injury that occurs following the initial trauma. This secondary injury is the result of a complicated sequence of events initiated by the release of neurotoxic and endogenous inflammatory mediators by resident cells of the central nervous system. In SCI, secondary tissue damage and lesion expansion involve inflammatory events such as ischemia, oxidative damage, inflammatory cell infiltration and necrotic and apoptotic cell death. In TBI, microglia and astrocytes can produce pro-inflammatory cytokines and chemokines, together with the infiltrated leukocytes through the damaged bloodbrain barrier. Despite different pathologies, an immunomodulatory therapeutic targeted at reducing the negative aspects of neuroinflammation may produce comparable efficacy in minimizing the extent of the secondary injury following the initial insult in TBI and SCI patients, along with related indications such as systemic inflammatory response syndrome (SIRS).

There is a significant unmet need to develop therapeutics for SCI and TBI in both the civilian and military populations. Many programs have shown promising results in pre-clinical trials but all have failed in humans. Accordingly, there is ongoing desire to develop new therapeutic approaches to treat TBI and SCI.

Tech Overview

Robarts Research Institute researchers at Western University have developed a suite of neuroprotective monoclonal antibodies targeting CD11d which plays a role in immune and inflammatory responses. CD11d is an important component of the CD11d/CD18 integrin expressed on the majority of circulating human neutrophils and monocytes/macrophages, NK, B and γδ T cells but not on αβT cells. Early treatment in animal (rat and mouse) models of SCI, TBI and SIRS prevents neuroinflammatory damage by neutrophils and macrophages resulting in improved neurological recovery. It is believed that these antibodies target CD11d expressed on the first wave of pro-inflammatory cells entering the wound site whereby neutrophil and macrophage accumulation is reduced, overall secondary injury-associated cell death is decreased and more neuronal tissue is spared further injury leading to better functional recovery.

Benefits

  • Therapeutic candidates identified to a novel target with potential for further lead optimization
  • Short treatment course immediately following injury
  • Treatment is non-depleting and short acting – patients should maintain functional immune system during recovery

Applications

  • Spinal cord injury
  • Traumatic brain injury
  • Additional potential applications (not yet investigated by Western): acute kidney injury, transplantation, heart lung bypass, subarachnoid hemorrhage, cervical spondylotic myelopathy, eosinophilic asthma, osteoarthritis, cardiovascular disease other than atherosclerosis.

Greg Dekaban, PhD

Dekaban’s expertise is in developing immunotherapeutics that prevent or modify disease outcomes. His most recent efforts focused on characterizing the cellular inflammatory response to spinal cord injury and developing an antibody-based therapy to block leukocyte infiltration into the injured spinal cord. His research will contribute to a better understanding of the natural history of brain injury.

Artificial Placenta

Improved Postnatal Gas Exchange in Newborn Infants with Severe Form of Respiratory Failure

Background

Lungs perform gas exchange for the human body. In preterm infants, this lung function is impaired, and respiratory distress syndrome (RDS) is the major cause of mortality in neonates (newborn infants under 4 weeks old). Typical clinical routine utilizes mechanical ventilation to support the lungs in oxygenating blood or ECMO (extracorporeal membrane oxygenation) for gas exchange. However, in preterm and term neonates, both strategies are associated with complications. Mechanical ventilation damages the thin lining of the lung and under critically ill conditions (RDS, sepsis, and pneumonia), is insufficient to prevent death or long-term impairment. Currently, ECMO is invasive and requires surgery to connect the device directly to the central blood vessels and high priming volume, needing external blood addition and pump.

The present invention provides the world’s first passive lung assist device that is designed to be pumped by the baby’s heart and capable of gas exchange in ambient air; a concept termed as the artificial placenta. This novel artificial oxygenation device is pumpless, easy-to-use and miniaturized for neonates (to minimize the risk of excessive blood loss). The device can be connected to the umbilical vessels, is biocompatible and minimizes damage to blood cells. The device has been demonstrated in animal trials and is capable of supporting the needs of a 1-2 kg neonate and increase blood oxygen saturation from 70 – 100%.

Advantages

  • Provides gas exchange by imitating the placental function in order to prevent damage to the premature lung
  • Passive – Pumped by the baby’s own heart and exchanges oxygen with the ambient environment

Applications

  • Artificial placenta to improve postnatal gas exchange in newborn infants with severe form of respiratory failure

Dr. Christoph Fusch

Fusch is a Pediatric Neonatologist and chief physician of the clinic for newborns, children and adolescents at the Nuremberg Clinic. Previously, he was a Professor in Pediatrics at McMaster University. He has more than 15 years of extensive experience in improving short- and long-term outcomes of premature infants and high-risk term neonates which has resulted in more than 100 publications. Over the past ten years, he has been developing of a microfluidic artificial placenta, dual ex-vivo closed-loop placenta perfusion, and optimizing nutrition and growth of very low birth weight (VLBW) infants.

Ravi Selvaganapathy, PhD

Selvaganapathy is a Professor in Mechanical Engineering and Canada Research Chair in Biomicrofluidics. He has over 20 years of experience in microfabrication and microfluidics. His research interests are in the development of microfluidic devices for drug discovery, drug delivery, diagnostics and artificial organs. He has more than ~80 publications, in the top journals in the field. Three of his inventions have been commercialized.

Team

In addition, the team consists of Dr. John Brash, Dr. Niels Rochow (Pediatric Neonatologist), Dr. Gehard Fusch (Analytical Chemist), MohammedHussein Dabaghi (Microfabrication/microfluidics Engineer), Shelley Monkman (Animal Experiment Specialist).

Design for Manufacturing Methodologies to Fabricate Large Components using the Fused Deposition Modelling Process

A process of layering or additive manufacturing that builds a component from thin layers by heating and extruding thermoplastic filament.

Background

  • Fused Deposition Modelling (FDM) ‑ A process of layering or additive manufacturing that builds a component from thin layers by heating and extruding thermoplastic filament
  • Each layer is a 2D slice ( Figure 1 ) of a 3D component ( Figure 2 ) and is stacked successively to fabricate the component
  • Additional material is often required to generate support structures for undercuts and overhanging geometry
  • The support material needs to be removed once the fabrication of the component is complete
  • Large components need to be broken-down into sub-components due to size limitations of the build envelope (or build area)
  • There is a need for optimization strategies to minimize material usage, build times and surface finish variations

Tech Overview

  • Novel methodologies to facilitate fabrication using design for fused deposition modeling (DfFDM) and design for FDM assembly (DfFDMA).
  • Uses construction geometry and/or segmentation and connectivity strategies to increase throughput and reduce fabrication costs.
Fabricating a Vented Enclosure Cover Using Construction Geometry
  • Cover is divided into segments, including L and R wings
  • Two configurations are presented for L and R wings: 4 supports and 10 supports
  • Compared build time and total material used for both configurations vs. standard
  • Build time is reduced by 11 hours for the 10 wall per wing configuration, and 15 hours for the 4 wall per wing configuration ( Figure 3 ).
  • Increasing the build material by ~ 60% reduced the overall amount of material used by ~50% or over 620 cm3 ( Figure 4 ).
Fabricating a Gear Case Using DfFDMA methodology
  • Component is split into 3 sub-sections
  • Sub-components are re-packaged to minimize support material
  • Approximately 500 cm3 or 66% less support material is required for the basic support option, and 200 cm3 or 57% less support material is required for the sparse support build options ( Figure 5 ).
  • Figure 6 ‑ Workflow

Applications

  • Thin shelled components where significant amounts of support material are required
  • Large components where segmentation may be required

Jill Urbanic, PhD

Urbanic has been involved with design, implementation, and support for several types of manufacturing, material handling, testing, gauging and assembly equipment for a variety of engine components and vehicle styles. She is an Associate Professor in the Department of Mechanical, Automotive, and Materials Engineering at UWindsor, and teaches courses related to design and technical communication, such as systems design, computer aided design and manufacturing, and senior design projects.

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