Panelists: Burak Ozdoganlar, Carnegie Mellon University; Susan Daniel, Cornell University; Merlin Bruening, University of Notre Dame
Live Panel Discussion III: Fundamentals/Therapeutics
Written by Jessalyn Low Hui Ying
Three panelists presented key research contributing to therapeutic strategies for fighting the ongoing COVID-19 pandemic. While in different areas, one unifying factor is that their materials research projects were done during this pandemic and notably builds on the prior body of knowledge and research done in their respective research groups. In the live panel discussion of this session, besides addressing keynote-specific questions, much insightful discussion was raised on how COVID-19 has influenced the way research is done and public perception of science.
One key recurring idea in this panel discussion is how fighting COVID-19 is a multidisciplinary problem that requires much interdisciplinary collaboration between clinicians, biologists, materials engineers, computer scientists, and many other specialists. This is especially so as to achieve engineering solutions in a quick amount of time like in the case of pandemics, as well as to drive conversations and seek inspiration on how one’s expertise can be leveraged for achieving solutions for COVID-19. For example, Burak Ozdoganlar shared how their lab has been developing their microneedle array technology prior to COVID-19, but not for the delivery of vaccines. After building a collaboration with the Center for Vaccine Research at the University of Pittsburgh, conversation was generated on how their microneedle array technology can be used to deliver live attenuated viruses, which started the transition into research work for COVID-19. Susan Daniel also mentions how biology exhibits a strong structural-functional relationship and raises the possibility of using artificial intelligence to establish such relationships instead of achieving them empirically.
However, it is not only such scientific and technical collaborations that are important. Merlin Bruening points out that to realize the potentials of translational research, collaboration with industry and companies is essential to commercializing technology developed in academia. This is especially so to bring out technology rapidly, given the timescale of COVID-19. To this end, session co-chair Kaitlyn Sadtler highlights the importance of science communication to explain discipline-specific work to people from other fields, which also ties into public trust in science.
In fact, this pandemic has brought about many opportunities. COVID-19 has shown how researchers can be creative and adapt their research for advancing knowledge and technology in this pandemic, such as in therapeutics, diagnostic tools, and personal protective equipment. More importantly, researchers have built the body of work essential for preparedness for future pandemics, should this happen. Research and implementation, however, is a long-drawn preposition, as Ozdoganlar points out. He notes that for this, sustained good amounts of funding is critical for researchers to continue progressing with this work even when the COVID-19 pandemic subsides, to deliver something that is clinically relevant.
The panel discussion also raised insights on how COVID-19 has influenced the public perception of science and demonstrated how science is important in managing this pandemic. Bruening raises the fact that it is basic science and the fundamental discoveries in the past 20 years or so that has led to many scientific advances today like in therapeutics for tackling COVID-19. Besides this, Daniel also highlights how COVID-19 has drawn importance to the need for managing public health, other than personalized medicine which has been a huge focus pre-COVID-19. This underlies the fact that people and communities are deeply interconnected, leading to session co-chair Elizabeth Wayne pointing out, too, the importance of sociocultural dynamics in fighting COVID-19.
Kaitlyn Sadtler of the National Institutes of Health and Elizabeth Wayne of Carnegie Mellon University co-chaired this session, which can be viewed online through December 31st. Following are reports on each panelist prior to the discussion.
Burak Ozdoganlar, Carnegie Mellon University
Microneedles Arrays for Effective and Efficient Mass Vaccinations
An effective vaccination strategy, especially in the wake of COVID-19, should involve a potent vaccine and an efficient delivery system. Traditional vaccine delivery approaches via intramuscular or subcutaneous routes have many disadvantages, in particular requiring high doses. The skin, however, has a robust immune network that can be leveraged for vaccine delivery. In this talk, Burak Ozdoganlar presents an intradermal delivery strategy using dissolvable microneedle arrays (MNAs) developed by his research group.
MNAs involve hundreds of microsized needles fabricated in a patch form, and for dissolvable MNAs, these needles are formed from a mixture of dissolvable sugar-based material and biocargo. The fabrication of dissolvable MNAs involves a diamond micromilling process to achieve precise geometries and with high reproducibility. Upon insertion into the skin, the MNAs dissolve and deliver the biocargo into the skin, a process which takes only 10-15 minutes. These dissolvable MNAs for intradermal delivery of biologics host many advantages over traditional techniques (Mantoux technique), including being dose-sparing, reproducible, and pain-free. In vivo and ex vivo studies demonstrated the successful delivery of siRNAs and adeno-associated virus (AAV) vectors using this technology. Ozdoganlar mentions that there are, however, certain drawbacks that may affect the scalability of using dissolvable MNAs for clinical vaccination, in particular sterilization, which could affect the viability of vaccines; regulation challenges, whereby new FDA approval must be attained for each vaccine; and interference of dissolvable materials with presentation of vaccines.
Ozdoganlar therefore next presents in his talk a novel next-generation system – hybrid MNAs. Here, the microneedle tips remain dissolvable, but cannulas are non-dissolvable. Instead, these cannulas connect to a reservoir of vaccines which allow for the continued delivery of vaccines from the backside upon dissolution of the tips when inserted. Having the vaccines in a reservoir provides many advantages, including being able to deliver any type of vaccine like live attenuated viruses, co-delivery of adjuvants, and non-influence of sterilization on vaccine bioactivity. In short, these hybrid MNAs retain all advantages yet addresses problems of dissolvable MNAs. This brings about immense potential for achieving a scalable and effective vaccine delivery system for global immunization programs.
Susan Daniel, Cornell University
Insight from the Physical Sciences on Coronavirus Host Entry and Therapeutic Interventions
For coronaviruses (CoV), the fusion of the virus and host cell membrane is mediated by the spike protein (S). Particularly, the fusion peptide (FP) within S interacts with the host cell membrane and plays a key role for viral genome transfer. Therefore, if the FP interaction with host membrane is inhibited, it may bring about significant advances in developing therapies against coronaviruses such as SARS-CoV-2, as in the case of COVID-19. In this talk, Susan Daniel presents her research team’s work on understanding the impact of calcium binding on CoV infection.
Daniel explains in this talk that the idea behind this was observing how the FP sequence is highly conserved across different coronavirus types like SARS-CoV and SARS-CoV-2, and in this sequence, runs of charged residues are present, which led the researchers to hypothesize whether calcium ions (Ca2+), which are fusiogens in other cellular processes, interact with charged residues of FP. In fact, cell infectivity studies using SARS-CoV showed that infectivity increased with Ca2+. To gain physical insight into this mechanism, various biophysical studies were done. Results showed that Ca2+ promotes the structural organization and alpha-helix stability of FP, which increases FP membrane insertion and lipid ordering of the host membrane. This is a precursor for membrane fusion to occur, associated with increased infectivity. In fact, isothermal calorimetry studies showed that Ca2+ interact directly with FP and knockout studies show that the charged residues of FP are indeed critical for calcium binding and infection.
With such knowledge that Ca increases CoV infection, the researchers tested if calcium channel blockers, typically used for treating cardiac disorders, can similarly limit SARS-CoV-2 infection. In vitro studies showed that some did successfully limit infection. Daniel explains that more studies are still needed, but these preliminary results indicate the potential for repurposing calcium channel blockers for the treatment of COVID-19.
Merlin Bruening, University of Notre Dame
Membrane Based Affinity Capture to Quantify Antibodies to COVID-19
Antibody detection and quantification are essential for the management of viruses, especially in the case of pandemics where many clinical and public health decisions need to be made. In this talk, Merlin Bruening presents a porous membrane system that can be used to quantify antibodies which can be used for COVID-19.
Bruening first explains the working principle behind this. These membranes are functionalized through a layer-by-layer deposition function to deposit polyacrylic acid (PAA) which contains carboxyl (COOH) groups. These can then be used to immobilize affinity molecules and consequently capture the antibodies of interest when serum is passed through the membrane. After rinsing, the elute can then be quantified to determine the antibody concentration. This is because when the researchers used a peptide mimotope to bind the monoclonal antibody Avastin, the elute was pure and showed high specificity. Fluorescence quantification of eluted Avastin gave a linear calibration curve and showed high recovery of Avastin, which indicates that this membrane-based affinity capture technique can be used for rapid absolute quantification of antibodies.
Bruening also further presents two different membrane-based designs that leverage on the same principle, but with a simpler design for antibody quantification. The first design is achieved via spotting the affinity molecules at the center of the membrane, then passing through fluorescence-labeled secondary antibodies after first passing through the serum with antibodies. In this way, the antibody concentration, which is proportional to fluorescence signal, can be analyzed directly from the membrane without a need for elution. The second design he talked about also uses fluorescence-labeled secondary antibodies, but this time, the entire 96-well plate is modified with the membrane at the bottom. In this way, no membrane holder is needed.
Bruening ends his talk showing how this membrane system can be used for the detection of monoclonal antibodies against COVID-19. To this end, they immobilized SARS-CoV-2 receptor-binding domain (RBD) proteins via amide bonds to the membrane and results showed that the absolute concentration of SARS-CoV-2 monoclonal antibodies could be quantified from conjugated fluorescence-labeled secondary antibodies. These studies highlight how this membrane system can enable rapid antibody quantification, even at the µg to ng/mL level.
For more MRS Meeting Scene coverage of materials approaches for attacking COVID-19, see: