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Associate Professor

Specialty Areas:

Mucus Structure, Rheology, and Flow; Mucus Adhesion; Cilia Force Generation

Research Focus:

During normal respiration, thousands of bacteria and other airborne irritants are inhaled every hour. Despite this constant intake of pathogens, the body is able to maintain sterility in the airways below the larynx. The task of accomplishing this feat falls to the protect airway surface liquid layer, a two-phase liquid consisting of a viscoelastic mucus layer as well as the periciliary liquid layer through which cilia beat, clearing mucus from the airways. In diseases such as cystic fibrosis, the mucus layer becomes increasing solid-like, leading to a decrease in mucus clearance as well as an increased rate of infection. In order to understand the phenomena of mucociliary clearance, it is necessary to understand the physical properties of the mucus layer as well as the driving forces that propel the fluid: the pressure gradient consistent with normal tidal breathing and the forces imparted on the mucus layer by cilia. It is the goal of my research to characterized and model the airway surface liquid in terms of its physical properties, chemical composition, flow, and response to pathogenic material.The primary interest of my research is Mucociliary clearance and how it is affected by diseases such as Cystic Fibrosis and Chronic Sinusitis.

Research Projects:

  • Mucus Rheology: Employing the techniques of microbead rheology, cone and plate, and driven magnetic bead rheology, the goal of this project is to determine the physical properties of mucus so that the fluid can be successfully modeled
  • Three Dimensional Force Microscope (3DFM): The 3DFM allow us to evaluate the viscoelastic modulus of fluids to viscous to be studied with Microbead Rheology, apply forces directly to biological systems (CF Mucus, ActA, and beating cilia), and map the topography of entangled mess networks often found in viscoelastic fluids
  • Cilia induced Stress-Strain in Mucus: The motion of tracer particles is examined to determine the amount of deformation imposed on mucus by cilia and examine how the deformation is propagated thru the fluid.
  • Modeling mucus flow and small molecule diffusion: Experimental results are used to determine the correct constitutive laws to model and predict small molecule diffusion and mucus flow.
  • Micro-Parallel Plate Rheometer (MPPR): The MPPR is an optically based rheometer that determines the bulk viscoelastic properties of fluids using quintiles less than 10uL.

Selected Bibliography:

  1. Greenwald MA, Meinig SL, Plott LM, Roca C, Higgs MG, Vitko NP, Markovetz MR, Rouillard KR, Carpenter J, Kesimer M, Hill DB, Schisler JC, Wolfgang MC. Mucus polymer concentration and in vivo adaptation converge to define the antibiotic response of Pseudomonas aeruginosa during chronic lung infection. mBio. 2024 Apr 23:e0345123. doi: 10.1128/mbio.03451-23. Epub ahead of print. PMID: 38651896.
  2. Dougherty GW, Ostrowski LE, Nöthe-Menchen T, Raidt J, Schramm A, Olbrich H, Yin W, Sears PR, Dang H, Smith AJ, Beule AG, Hjeij R, Rutjes N, Haarman EG, Maas SM, Ferkol TW, Noone PG, Olivier KN, Bracht DC, Barbry P, Zaragosi LE, Fierville M, Kliesch S, Wohlgemuth K, König J, George S, Loges NT, Ceppe A, Markovetz MR, Luo H, Guo T, Rizk H, Eldesoky T, Dahlke K, Boldt K, Ueffing M, Hill DB, Pang YP, Knowles MR, Zariwala MA, Omran H. Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis. Am J Respir Crit Care Med. 2024 Apr 16. doi: 10.1164/rccm.202308-1370OC. Epub ahead of print. PMID: 38626355.
  3. Rouillard KR, Esther CP, Kissner WJ, Plott LM, Bowman DW, Markovetz MR, Hill DB. Combination treatment to improve mucociliary transport of Pseudomonas aeruginosa biofilms. PLoS One. 2024 Feb 23;19(2):e0294120. doi: 10.1371/journal.pone.0294120. PMID: 38394229; PMCID: PMC10890754.
  4. Donoghue LJ, Markovetz MR, Morrison CB, Chen G, McFadden KM, Sadritabrizi T, Gutay MI, Kato T, Rogers TD, Snead JY, Livraghi-Butrico A, Button B, Ehre C, Grubb BR, Hill DB, Kelada SNP. BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance. Am J Physiol Lung Cell Mol Physiol. 2023 Dec 1;325(6):L765-L775. doi: 10.1152/ajplung.00390.2022. PMID: 37847709.
  5. Ozeri-Galai E, Friedman L, Barchad-Avitzur O, Markovetz MR, Boone W, Rouillard KR, Stampfer CD, Oren YS, Hill DB, Kerem B, Hart G. Delivery Characterization of SPL84 Inhaled Antisense Oligonucleotide Drug for 3849 + 10 kb C- > T Cystic Fibrosis Patients. Nucleic Acid Ther. 2023 Oct;33(5):306-318. doi: 10.1089/nat.2023.0015. PMID: 37643307.
  6. Hill DB. Editorial: Mucus and the mucociliary interface: continuity and clearance. Front Physiol. 2023 Jun 13;14:1233276. doi: 10.3389/fphys.2023.1233276. PMID: 37383143; PMCID: PMC10295136.
  7. Markovetz MR, Hibbard JE, Plott LM, Bacudio LG, Kissner WJ, Ghio A, Kumar PA, Arora H, Hill DB. Normalizing salt content by mixing native human airway mucus samples normalizes sample rheology. Front Physiol. 2023 Mar 10;14:1111647. doi: 10.3389/fphys.2023.1111647. PMID: 36969580; PMCID: PMC10036356.
  8. Rouillard KR, Markovetz MR, Kissner WJ, Boone WL, Plott LM, Hill DB. Altering the viscoelastic properties of mucus-grown Pseudomonas aeruginosa biofilms affects antibiotic susceptibility. Biofilm. 2023 Jan 21;5:100104. doi: 10.1016/j.bioflm.2023.100104. PMID: 36711323; PMCID: PMC9880403.
  9. Markovetz MR, Garbarine IC, Morrison CB, Kissner WJ, Seim I, Forest MG, Papanikolas MJ, Freeman R, Ceppe A, Ghio A, Alexis NE, Stick SM, Ehre C, Boucher RC, Esther CR, Muhlebach MS, Hill DBMucus and mucus flake composition and abundance reflect inflammatory and infection status in cystic fibrosis. J Cyst Fibros. 2022 Nov;21(6):959-966. doi: 10.1016/j.jcf.2022.04.008. PMID: 35437233.
  10. Hill DB, Button B, Rubinstein M, Boucher RC. Physiology and Pathophysiology of Human Airway Mucus. Physiol Rev. 2022 Oct 1;102(4):1757-1836. doi: 10.1152/physrev.00004.2021. PMID: 35001665. PMCID: PMC9665957.
  11. Rouillard KR, Kissner WJ, Markovetz MR, Hill DB. Effects of Mucin and DNA Concentrations in Airway Mucus on Pseudomonas aeruginosa Biofilm Recalcitrance. mSphere. 2022 Aug 31;7(4):e0029122. doi: 10.1128/msphere.00291-22. PMID: 35968965; PMCID: PMC9429933.
  12. Varma DM, Batty CJ, Stiepel RT, Graham-Gurysh EG, Roque JA 3rd, Pena ES, Hasan Zahid MS, Qiu K, Anselmo A, Hill DB, Ross TM, Bachelder EM, Ainslie KM. Development of an Intranasal Gel for the Delivery of a Broadly Acting Subunit Influenza Vaccine. ACS Biomater Sci Eng. 2022 Apr 11;8(4):1573-1582. doi: 10.1021/acsbiomaterials.2c00015. PMID: 35353486. PMCID: PMC9627116.
  13. Kato T, Radicioni G, Papanikolas MJ, Stoychev GV, Markovetz MR, Aoki K, Porterfield M, Okuda K, Barbosa Cardenas SM, Gilmore RC, Morrison CB, Ehre C, Burns KA, White KK, Brennan TA, Goodell HP, Thacker H, Loznev HT, Forsberg LJ, Nagase T, Rubinstein M, Randell SH, Tiemeyer M, Hill DB, Kesimer M, O’Neal WK, Ballard ST, Freeman R, Button B, Boucher RC. Mucus concentration-dependent biophysical abnormalities unify submucosal gland and superficial airway dysfunction in cystic fibrosis. Sci Adv. 2022 Apr;8(13):eabm9718. doi: 10.1126/sciadv.abm9718. PMID: 35363522.
  14. Morrison CB, Shaffer KM, Araba KC, Markovetz MR, Wykoff JA, Quinney NL, Hao S, Delion MF, Flen AL, Morton LC, Liao J, Hill DB, Drumm ML, O’Neal WK, Kesimer M, Gentzsch M, Ehre C. Treatment of cystic fibrosis airway cells with CFTR modulators reverses aberrant mucus properties via hydration. Eur Respir J. 2022 Feb 3;59(2):2100185. doi: 10.1183/13993003.00185-2021. PMID: 34172469. PMCID: PMC8859811.
  15. Costain G, Liu Z, Mennella V, Radicioni G, Goczi AN, Albulescu A, Walker S, Ngan B, Manson D, Vali R, Khan M, Palaniyar N, Hill DB, Hall DA, Marshall CR, Knowles M, Zariwala MA, Kesimer M, Dell SD. Hereditary Mucin Deficiency Caused by Biallelic Loss-of-Function of MUC5B. Am J Respir Crit Care Med. 2022 Apr 1;205(7):761-768. doi: 10.1164/rccm.202106-1456OC. PMID: 35023825. PMCID: PMC9836224.
  16. Howard RL, Markovetz M, Wang Y, Ehre C, Sheikh SZ, Allbritton NL, Hill DB. Biochemical and rheological analysis of human colonic culture mucus reveals similarity to gut mucus. Biophys J. 2021 Dec 7;120(23):5384-5394. doi: 10.1016/j.bpj.2021.10.024. PMID: 34695384. PMCID: PMC8715165.
  17. Ford AG, Cao XZ, Papanikolas MJ, Kato T, Boucher RC, Markovetz MR, Hill DB, Freeman R, Forest MG. Molecular Dynamics Simulations to Explore the Structure and Rheological Properties of Normal and Hyperconcentrated Airway Mucus. Stud Appl Math. 2021 Nov;147(4):1369-1387. doi: 10.1111/sapm.12433. PMID: 35221375; PMCID: PMC8871504.
  18. Sears PR, Bustamante-Marin XM, Gong H, Markovetz MR, Superfine R, Hill DB, Ostrowski LE. Induction of ciliary orientation by matrix patterning and characterization of mucociliary transport. Biophys J. 2021 Apr 20;120(8):1387-1395. doi: 10.1016/j.bpj.2021.01.041. PMID: 33705757. PMCID: PMC8105732.
  19. Rouillard KR, Hill DB, Schoenfisch MH. Antibiofilm and mucolytic action of nitric oxide delivered via gas or macromolecular donor using in vitro and ex vivo models. J Cyst Fibros. 2020 Nov;19(6):1004-1010. doi: 10.1016/j.jcf.2020.03.004. PMID: 32205069. PMCID: PMC7502430.
  20. Rouillard KR, Markovetz MR, Bacudio LG, Hill DB, Schoenfisch MH. Pseudomonas aeruginosa Biofilm Eradication via Nitric Oxide-Releasing Cyclodextrins. ACS Infect Dis. 2020 Jul 10;6(7):1940-1950. doi: 10.1021/acsinfecdis.0c00246. PMID: 32510928.
  21. Schiller JL, Fogle MM, Bussey O, Kissner WJ, Hill DB, Lai SK. Antibody-mediated trapping in biological hydrogels is governed by sugar-sugar hydrogen bonds. Acta Biomater. 2020 Apr 15;107:91-101. doi: 10.1016/j.actbio.2020.03.002. PMID: 32147470. PMCID: PMC8812814.
  22. Ramsey KA, Chen ACH, Radicioni G, Lourie R, Martin M, Broomfield A, Sheng YH, Hasnain SZ, Radford-Smith G, Simms LA, Burr L, Thornton DJ, Bowler SD, Livengood S, Ceppe A, Knowles MR, Noone PG, Donaldson SH, Hill DB, Ehre C, Button B, Alexis NE, Kesimer M, Boucher RC, McGuckin MA. Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis. Am J Respir Crit Care Med. 2020 Mar 15;201(6):661-670. doi: 10.1164/rccm.201906-1219OC. PMID: 31765597. PMCID: PMC7068838.
  23. Markovetz MR, Subramani DB, Kissner WJ, Morrison CB, Garbarine IC, Ghio A, Ramsey KA, Arora H, Kumar PA, Nix DB, Kumagai T, Krunkosky TM, Krause DC, Radicioni G, Alexis NE, Kesimer M, Tiemeyer M, Boucher RC, Ehre C, Hill DB. Endotracheal Tube Mucus as a Source of Airway Mucus for Rheological Study. Am J Physiol Lung Cell Mol Physiol. 2019 Oct 1;317(4):L498-L509. doi: 10.1152/ajplung.00238.2019. PMID: 31389736. PMCID: PMC6842913.
  24. Ahonen MJR, Hill DB, Schoenfisch MH. Nitric oxide-releasing alginates as mucolytic agents. ACS Biomater Sci Eng. 2019 Jul 8;5(7):3409-3418. doi: 10.1021/acsbiomaterials.9b00482. PMID: 32309634. PMCID: PMC7164775.
  25. Esther CR Jr, Muhlebach MS, Ehre C, Hill DB, Wolfgang MC, Kesimer M, Ramsey KA, Markovetz MR, Garbarine IC, Forest MG, Seim I, Zorn B, Morrison CB, Delion MF, Thelin WR, Villalon D, Sabeter JR, Turkovic L, Ranganathan S, Stick SM, Boucher RC, on behalf of AREST CF. Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis. Sci Transl Med. 2019 Apr 3;11(486). doi: 10.1126/scitranslmed.aav3488. PMID: 30944166. PMCID: PMC6566903.
  26. Ehre C, Rushton ZL, Wang B, Hothem LN, Morrison CB, Fontana NC, Markovetz MR, Delion MF, Kato T, Villalon D, Thelin WR, Esther CR Jr, Hill DB, Grubb BR, Livraghi-Butrico A, Donaldson SH, Boucher RC. An Improved Inhaled Mucolytic to Treat Airway Muco-Obstructive Diseases. Am J Respir Crit Care Med. 2019 Jan 15;199(2):171-180. doi: 10.1164/rccm.201802-0245OC. PMID: 30212240. PMCID: PMC6353008.
  27. Hancock LA, Hennessy CE, Solomon GM, Dobrinskikh E, Estrella A, Hara N, Hill DB, Kissner WJ, Markovetz MR, Grove Villalon DE, Voss ME, Tearney GJ, Carroll KS, Shi Y, Schwarz MI, Thelin WR, Rowe SM, Yang IV, Evans CM, Schwartz DA. Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice. Nat Commun. 2018 Dec 18;9(1):5363. doi: 10.1038/s41467-018-07768-9. PMID: 30560893. PMCID: PMC6299094.
  28. Hill DB, Long RF, Kissner WJ, Atieh E, Garbarine IC, Markovetz MR, Fontana NC, Christy M, Habibpour M, Tarran R, Forest MG, Boucher RC, Button B. Pathological Mucus and Impaired Mucus Clearance in Cystic Fibrosis Patients Results from Increased Concentration, not altered pH. Eur Respir J. 2018 Dec 6;52(6). doi: 10.1183/13993003.01297-2018. PMID: 30361244. PMCID: PMC6446239.
  29. Zhang K, Crizer KPR, Schoenfisch MH, Hill DB, Didier G. Fluid heterogeneity detection based on the asymptotic distribution of the time-averaged mean squared displacement in single particle tracking experiments. J Phys A Math Theor. 2018 Nov 2;51(44). doi: 10.1088/1751-8121/aae0af. PMID: 31037119. PMCID: PMC6486181.
  30. Carpenter J, Lynch SE, Cribb JA, Kylstra S, Hill DB, Superfine R. Buffer drains and mucus is transported upward in a tilted mucus clearance assay. Am J Physiol Lung Cell Mol Physiol. 2018 Nov 1;315(5):L910-L918. doi: 10.1152/ajplung.00274.2018. PMID: 30211652. PMCID: PMC6295511.
  31. Meng H, Lockshin C, Jain S, Shaligram U, Martinez J, Genkin D, Hill DB, Ehre C, Clark D, Hoppe H. Clinical application of polysialylated therapeutic proteins. Recent Pat Drug Deliv Formul. 2018;12(3):212-222. doi: 10.2174/1872211312666180717164758. PMID: 30019653.
  32. Youngren-Ortiz SR, Hill DB, Hoffmann PR, Morris KR, Barrett EG, Forest MG, Chougule MB. Development of optimized, inhalable, gemcitabine-loaded gelatin nanocarriers for lung cancer. J Aerosol Med Pulm Drug Deliv. 2017 Oct;30(5):299-321. doi: 10.1089/jamp.2015.1286. PMID: 28277892. PMCID: PMC5650720.
  33. Reighard KP, Ehre C, Rushton Z, Ahonen M, Hill DB, Schoenfisch M. Role of nitric oxide-releasing chitosan oligosaccharides on mucus viscoelasticity. ACS Biomater Sci Eng. 2017;3(6):1017–26. doi: 10.1021/acsbiomaterials.7b00039. PMID: 30320206. PMCID: PMC6178828.
  34. Esther CR, Hill DB, Button B, Shi S, Jania CM, Duncan EA, Doerschuk CM, Chen G, Ranganathan S, Stick SM. The sialic acid to urea ratio as a measure of airway surface hydration. Am J Physiol Lung Cell Mol Physiol. 2017;312(3):L398-404. doi: 10.1152/ajplung.00398.2016. PMID: 28062483; PMCID: PMC5374301.
  35. Blackmon R, Kreda S, Sears P, Chapman B, Hill DB, Tracy J, Ostrowski L, Oldenburg A. Direct monitoring of pulmonary disease treatment biomarkers using plasmonic gold nanorods with diffusion-sensitive OCT. Nanoscale. 2017;9(15):4907-17. doi: 10.1039/c7nr00376e. PMID: 28358158; PMCID: PMC5473168.
  36. Vasquez PA, Jin Y, Palmer E, Hill DB, Forest MG. Modeling and simulation of mucus flow in human bronchial epithelial cell cultures–Part I: Idealized axisymmetric swirling flow. PLoS Comput Biol. 2016;12(8):e1004872. doi: 10.1371/journal.pcbi.1004872. PMID: 27494700; PMCID: PMC4975472.
  37. Mellnik JW, Lysy M, Vasquez PA, Pillai NS, Hill DB, Cribb J, McKinley SA, Forest MG. Maximum likelihood estimation for single particle, passive microrheology data with drift. J Rheol (1978-present). 2016;60(3):379-92. doi: 10.1122/1.4943988.
  38. Lysy M, Pillai NS, Hill DB, Forest MG, Mellnik JW, Vasquez PA, McKinley SA. Model comparison and assessment for single particle tracking in biological fluids. J Am Stat Assoc. 2016;111(516):1413-26. doi: 10.1080/01621459.2016.1158716.
  39. Reighard KP, Hill DB, Dixon GA, Worley BV, Schoenfisch MH. Disruption and eradication of P. aeruginosa biofilms using nitric oxide-releasing chitosan oligosaccharides. Biofouling. 2015;31(9-10):775-87. doi: 10.1080/08927014.2015.1107548. PMID: 26610146; PMCID: PMC4695972.
  40. Mellnik J, Vasquez PA, McKinley SA, Witten J, Hill DB, Forest MG. Micro-heterogeneity metrics for diffusion in soft matter. Soft Matter. 2014;10(39):7781-96. doi: 10.1039/c4sm00676c. PMID: 25144347; PMCID: 4186960.
  41. Chhetri RK, Blackmon RL, Wu WC, Hill DB, Button B, Casbas-Hernandez P, Troester MA, Tracy JB, Oldenburg AL. Probing biological nanotopology via diffusion of weakly constrained plasmonic nanorods with optical coherence tomography. Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):E4289-97. doi: 10.1073/pnas.1409321111. PMID: 25267619; PMCID: PMC4205670.
  42. Levy R, Hill DB, Forest MG, Grotberg JB. Pulmonary fluid flow challenges for experimental and mathematical modeling. Integr Comp Biol. 2014 Dec;54(6):985-1000. doi: 10.1093/icb/icu107. PMID: 25096289; PMCID: PMC4296202.
  43. Hill DB, Vasquez PA, Mellnik J, McKinley SA, Vose A, Mu F, Henderson AG, Donaldson SH, Alexis NE, Boucher RC, Forest MG.A biophysical basis for mucus solids concentration as a candidate biomarker for airways disease. PLoS One. 2014 Feb 18;9(2):e87681. doi: 10.1371/journal.pone.0087681. eCollection 2014. Erratum in: PLoS One. 2014;9(5):e97980. PMID: 24558372; PMCID: PMC3928107.
David Hill