Mathiowitz, Edith

Edith Mathiowitz

Professor of Pathology and Laboratory Medicine, Professor of Engineering

Overview

Dr. Edith Mathiowitz is a full Professor of Medical Science and Engineering at Brown University in the Department of Pathology and Laboratory Medicine. Her extensive experience includes development of polymers that are used in drug and gene delivery systems and tissue engineering applications. Following her undergraduate degree in physical chemistry and graduate school at the Weizmann institute of science, Dr. Mathiowitz trained as a postdoctoral associate with Professor Robert Langer.

Dr. Mathiowitz directs an interdisciplinary laboratory that focuses on developing smart delivery systems based on bioadhesive polymers, which enhance the non- specific interaction with intestinal mucosa by inducing reversible secondary bonds and prolonging the residence time of traditional and novel oral dosage forms. She has been a pioneer in the area of nanomedicine by developing spontaneously forming biodegradable nanoparticles that in contrast to traditional thinking that mucosal barrier will prevent those particles from even passing the mucosal tissue. They can be engineered by combining hydrophobic polymers with high concentration of carboxylic acid, penetrate mucosal barriers and deliver active biologics. These nanoparticles are being used as cancer vaccines as well as for the oral delivery of peptides and proteins. In addition, she has experience with polymers, vascular grafts and micro/nanoencapsulation. What characterize her work is using combination of basic scientific concepts in interfacial biophysics and applying them to improving health.

During her post doc, she submitted with Professor Langer seven patent applications of which 20 patents were issued and have subsequently been licensed to many startup companies. Her work at Enzytec generated four issued patents that form the basis for the Prolease delivery systems, injectable proteins such as growth hormones. Dr. Mathiowitz’s laboratory serves as a focal point for many inventions and as an incubator for several start-up companies. Some have licensed her technologies. Technologies she has developed have formed the foundation for the launch of four biotechnology companies, two of which Dr. Mathiowitz is a Founder: Spherics, Inc. – Founder; Perosphere, Inc. – Co-Founder. Dr. Mathiowitz was the Editor of The Encyclopedia of Controlled Drug Delivery Systems (1999) and serves as an editorial board member for several journals. In 2005, she was co-Chair of the Controlled Release Society, an international society dealing with drug delivery. To date, Dr. Mathiowitz has authored 120 publications, over 75 patents, and an edited book on bioadhesion; her work has been published in over 120 conference proceedings and abstracts. Her work at Brown University has generated about 56 patent applications of which 40 were issued as patents and have been the basis for two start-up companies and have been licensed to others.

Brown Affiliations

Research Areas

On the Web

Brown Professor Invents Diabetes Drug Delivery Method

Faculty inducted into the National Academy of Inventors

More intestinal cells can absorb larger particles

Polymers key to oral protein-based drugs

Research

Research Overview

Research in our laboratory focuses on the polymer science-medicine interface. Areas of interest include development and modeling of novel drug delivery systems, particularly for the release of insulin and growth factors; designing small-diameter vascular grafts with better compliance; development of novel bioadhesive polymers for oral delivery systems; liquid crystals as smart sensors; the use of nanoparticles as novel therapeutic delivery systems (nanomedicine), tissue markings, DNA delivery.

Research Statement

Research in our laboratory focuses on the interface between polymer science and biology. Areas of interest include:

Tissue engineering and drug ad gene delivery;
Development, modeling, and morphological analysis of novel drug delivery systems, particularly for the release of macromolecules, such as insulin and growth factors;
Synthesis and characterization of biomaterials for drug delivery systems;
Studies of polymer-protein interactions with emphasis in the development of bioerodible polymers involving the use of mild fabrication techniques;
Developing of bioadhesive polymers for use as oral delivery systems;
Design and development of modulated sensors that respond to external stimuli (e.g., light heat).

All of these studies are directed to create easier and more sophisticated ways to administer therapeutic agents into the body exactly where and when they are needed. Most therapeutic peptides and proteins easily degrade when taken orally and are too unstable to withstand packing in slow-release mechanisms - they all require frequent parenteral injections. Understanding the basics of delivery systems is the key for better medications in the future.

Studies of polymer-cell interaction, with particular emphasis on bioadhesion; development of the basic relationship between polymer structures (molecular and morphological) and living tissue; surface modification for enhancement of cell adhesion, an area of particular importance in the development of oral delivery systems as well as small vascular grafts.

Development of theoretical and experimental procedures to process microcapsules based on biomaterials; processing of polymeric composites based on microencapsulation. A wide range of polymers and polymer blends are investigated, including interpenetrating networks, amorphous, semicrystalline, and liquid crystal polymers.

Impact of work

Dr. Mathiowitz has worked on developing novel bioadhesive delivery systems. These systems range from basic engineering of fundamental science to the measurement of tensile forces between tissue/materials interactions, to designing smart delivery systems including the bioadhesive novel polymers.

The overall aim was to develop an effective oral delivery system for peptide and proteins based on safe, biocompatible, biodegradable, nanoparticles. Specifically developing engineered bioerodible nanoparticles that, once delivered to the mucosal tissue, are capable of penetrating the barrier, reach the epithelium, penetrate the cell and distribute to internal organs. This was achieved by developing an encapsulation technique, which first stabilizes sensitive proteins for delivery after oral delivery; the polymer then degrades thereby releasing the encapsulated protein. Additionally, nanoparticles were designed using a very specific bioadhesive coating that are capable of delivering the nanoparticles to intestinal tissue in order to enhance penetration and control the uptake. Recently, two major publication (PNAS, 2013 and JCR, 2013) from her lab demonstrated that the relatively high degree of microsphere uptake in the absorptive and non-absorptive epithelium indicates that endocytosis as well as phagocytotic mechanisms are responsible for MS uptake in the small intestine.

In addition, specific bioadhesive coatings can enhance particle uptake from 6% to 70%. The results of these studies provide strong support for the use of bioadhesive polymers to enhance nano- and microparticles uptake from the small intestine for oral drug delivery. This study, using nanoparticles as penetrating delivery systems demonstrated that the non-lymphoid tissue of the absorptive epithelium could absorb MS and facilitate their biodistribution throughout the rat. These findings may potentially guide research aimed at delivering specific molecules to target organs. In addition, the methods and in vivo model that was used may also be useful to toxicologists who are interested in determining the fate or tissue distribution of microparticles, including whether such particles can cross the blood-brain barrier.

In the area of microencapsulation, Dr. Mathiowitz’s work focuses on using basic concepts of polymer phase separation phenomenon to design self-assembled microspheres, vascular grafts and fiber reinforced by Solvent induced crystallization. One example is the development of Multi-walled microsphere (Nature 1994); many approaches for controlled release of drugs involves incorporation of the drug molecules into the matrix of microscopic polymer spheres or capsules. Those existing methods for preparing such micro-particles do not, however, always guarantee a constant release rate. For example, drug molecules may be trapped preferentially at the surface; they have to diffuse through an increasing thickness of polymer when the particles are non-eroding, or the surface area changes for eroding particles. In other situations, pulsed release may be required—an application to which simple polymer microspheres do not readily lend themselves. Dr. Mathiowitz’s work on how to engineer Multi-walled microspheres might solve some of these problems. She has developed a one-step process for preparing double-walled polymer microspheres based on phase separation between polymer mixtures, with an appropriate choice of interfacial tensions and evaporation rate, a spherical droplet of one polymer becomes coated with a highly uniform layer of the other.

Dr. Mathiowitz’s work resulted in major publications, but also translated into two starts-up companies, Spherics, Inc. and Perosphere, Inc., which focuses their efforts on developments to improve patient compliance.

Funded Research

Mathiowitz (Principal Investigator) 05/01/2004 to 08/31/2006
Source: Freedom2, LLC
Project Title: "Encapsulation of Dyes, Pigments, and Optically Active Substances for Use in Cell and Tissue Markings"

Project Number: R01 CA100656-01A1 05/1/2004 to 4/30/2006
Source: National Institutes of Health (NIH) Prime University of Louisville Subcontract
Role: Mathiowitz, E. (Investigator), Egilmez, Nejat (PI)
Project Title: "Integrating Innate & Adaptive Immunity in Cancer Therapy"

Mathiowitz (Principal Investigator) 7/1/2001 to 7/31/2005
Source: Spherics, Inc.
Project Title: "Oral Formulation of Large Bioadhesive Drug Delivery System"

Project No.: PHS 2 R01 EB00248-08 Mathiowitz (Principal Investigator) 5/1/1994 to 6/30/2005
Source: National Institutes of Health/National Institute of Biomedical Imaging and BioEngineering (NIH/NIBIB) (Formerly GM47636)
Project Title: "Bioadhesive Microspheres: Comparison in Rats and Pigs"

Project No: CA42278 Egilmez (Principal Investigator) 4/1/2001 to 3/31/2003
Source: Health Research Inc. (NIH Prime)
Role: Mathiowitz, E. (Investigator)
Project Title: "Oxygen and Light Dependency of Photodynamic Therapy"

Project Number: JDFI 4-1999-402 Mathiowitz (Principal Investigator) 4/1/1999 to 3/31/2002
Source: Juvenile Diabetes Foundation
Project Title: "Therapeutic Potential of Erodable Microspheres in IDDM"

Project No.: PHS 1 R01 GM55245-06 Mathiowitz (Principal Investigator) 8/1/1997 to 7/31/2002
Source: National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
Project Title: "Microspheres for Improved Bioavailability"

Scholarly Work

42. Lavin DM, Harrison, R. MW, Tee LY, Wei KA, Mathiowitz E..,Multifunctional polymeric microfibers with prolonged drug delivery and structural support capabilities.J Biomed Mater Res A. 2012 May 24.

41. Lavin DM, Harrison MW, Tee LY, Wei KA, Mathiowitz E.,A novel wet extrusion technique to fabricate self-assembled microfiber scaffolds for controlled drug delivery., J Biomed Mater Res A. 2012 May 24

43. Lavin DM, Hopkins, E. Mathiowitz," Effects of protein molecular weight on the intrinsic material properties and release kinetics of wet spun polymeric microfiber delivery" Acta Biomaterialia, ACTBIO2333, S1742-7061(12)00372-8, 10.1016/j.actbio.2012.08.00

39. Laulicht, B., Nicholas J Gidmark, Anubhav Tripathi, and Edith Mathiowitz., Understanding gastric forces calculated from high-resolution pill tracking. Proc Natl Acad Sci U S A, 2010. 107(18): p. 8201-6.

40. Bryan Laulicht, Nicholas J Gidmark, Anubhav Tripathi, and Edith Mathiowitz., Localization of magnetic pill. Proc Natl Acad Sci U S A, 2010

38. Laulicht, B., et al., Are in vivo gastric bioadhesive forces accurately reflected by in vitro experiments? J Control Release, 2009. 134(2): p. 103-10.

36. Jacklenec A, Hinkfuss A, Bilgen B, Ciombor DM, Aaron R, Mathiowitz E. Sequential release of bioactive IGF-I and TGF-beta(1) from PLGA microsphere-based scaffolds. Biomaterials 2008; (10): 1518-25.

34. Furtado S, Abramson D, Burrill R, Olivier G, Gourd C, Bubbers E, Mathiowitz, E. Oral delivery of insulin loaded poly(fumaric-co-sebacic) anhydride microspheres. Int J Pharm. 2008;347(1-2):149-55.

37. Laulicht B, Cheifetz P, Mathiowitz E, Tripathi A. Evaluation of continuous flow nanosphere formation by controlled microfluidic transport. Langmuir. 2008 Sep 2;24(17):9717-26. 2008 Aug 6.

33. Morello AP, 3rd, Forbes N, Mathiowitz E. Investigating the effects of surfactants on the size and hydrolytic stability of poly(adipic anhydride) particles. J Microencapsul 2007;24:40-56.

35. Stacia Furtado, Danielle Abramson, Liat Simhkay, Daniel Wobbekind, Edith Mathiowitz, Subcutaneous delivery of insulin loaded poly(fumaric-co-sebacic anhydride) microspheres to type 1 diabetic rats European Journal of Pharmaceutical and biopharmaceutics, Volume 62 , June 2006, Pages 229–236

32. N.A. Rahman, E. Mathiowitz. Localization of bovine serum albumin in double-walled microspheres. Journal of controlled release. 94,163-175, 2004.

31. CG Thanos, K-P. Yip, and E. Mathiowitz Intestinal Uptake of Polymeric Microspheres In The Rabbit Studies With Confocal Microscopy. Journal of Bioactive and Compatible Polymers, Vol. 19, July 2004: 247-266.

29. CG C Thanos, Z Liu, J Reineke, E Edwards and E Mathiowitz, Improving Relative Bioavailability of Dicumarol by Reducing Particle Size and Adding the Adhesive Poly (Fumaricˆco-Sebacic) Anhydride. Pharmaceutical Research. Volume 20, Number 7, July 2003; 1093-1100.

30. C Thanos, Z Liu, M Goddard, J Reineke, N Bailey, M Cross, R Burrill and E Mathiowitz, Enhancing the Oral Bioavailability of the Poorly Soluble Drug Dicumarol with a Bioadhesive Polymer. Journal of Pharmaceutical Sciences. Volume 92, Issue 8, May 2003; 1677-89.

28. M. Sandor, S Mehta, J Harris, C Thanos, J Marshall, P Weston "Transfection of HEK Cells via DNA-leaded PLGA and P(FASA)" J Drug Targeting, 10, 497-506, 2002.

27. M. Sandor, J Harris, E Mathiowitz, "A Novel Polyethylene Depot Device for the Study of PLGA Microspheres in Vitro and in Vivo" Biomaterials, 23,4413-4423, 2002.

26. NA Bailey, M Sandor, M Kreitz, E Mathiowitz, "Comparison of the Enthalpic Relaxation of Poly(Lactide-Co-Glycolide) 50:50 Nanospheres and Raw Polymer" J Applied Polymer Science, 86,1868-1872, 2002.

25. M.Sandor, NA Bailey, E Mathiowitz "Characterization of polyanhydride microsphere degradation by DSC," Polymers, 43/2, pp279-288, 2001

24. C.Santos, B.Freedman, K.Leach, D.Press, M.Scarpulla, E.Mathiowitz, "Polytumaric-co-sebacic anhydride:A Degradation Study as Evaluated by FTIR, DSC, GPC, and X-ray Diffraction". Journal of Controlled Release, 60 (1), 11-22, 1999

23. N.Egilmez, Y.Jong, J.Jacobs, C.Santos, E.Mathiowitz, Y.Iwanuma, R.Bankert, "Cytokine immunotherapy of cancer with controlled release biodegradable microspheres in a human tumor xenograft/SCID mouse model, Cancer Immunology Immunotherapy, 1998 Mar; 46(1):21-4.

22. W. Webber, F. Lago, and E. Mathiowitz, "Characterization of Soluble Salt Loaded Degradable PLA/PG Films and Their Release of Tetracycline," Biomedical Materials Research, 41, 18-29, 1998

20. Y. Jong, J. Jacob, K. Yip, G. Gardner, E. Seitelman, M. Whitney, S. Montgomery, and E. Mathiowitz, "Controlled Release of Plasmid DNA," J. of Controlled Releasee 47, 123-134, 1997.

19. E. Mathiowitz, J. Jacob, Y. Jong, G. Carino, D. Chickering, P. Chaturvedi, C. Santos, K. Vijayaraghavan, S. Montgomery, M. Bassett and C. Morrell, "Biologically Erodable Microspheres as Potential Oral Drug Delivery Systems," Nature 386, 410-414, 1997.

18. M. Kreitz, W. Webber, P.M.Galletti, and E. Mathiowitz, "Controlled Delivery of Therapeutics from Microporous Membranes I. Fabrication and Characterization of Microporous Polyurethane Membranes Containing Polymeric Microspheres," Biomaterials 18, 597-603, 1997.

17. Y. Jong, J. Jacob, K. Yip, G. Gardner, E. Seitelman, M. Whitney, S. Montgomery, and E. Mathiowitz, "Controlled Release of Plasmid DNA," J. Controlled Release, In press, 1997.

15. D. Chickering, J. Jacob and E. Mathiowitz, "Poly(Fumaric-co-Sebacic) Microspheres as Oral Drug Delivery Systems, "Biotechnology and Bioengineering, 52, 96-101, 1996.

16. K. Pekarek, M. Dyrud, K. Ferrer, Y. Jong, E. Mathiowitz, "In Vitro and In Vivo Degradation of Double-Walled Polymer Microspheres," J. Controlled Release, 40, 169-178, 1996.

14. D. Chickering, and E. Mathiowitz. "Bioadhesive microspheres: I. A Novel electrobalance-based method to study adhesive interactions between individual microspheres and intestinal mucosa," J. Controlled Release, 34, 251-261, 1995.

13. Pekarek, J. Jacob and E. Mathiowitz "Double-walled Microspheres for Controlled Drug Release," Nature, 367, 258-260, January 20, 1994.

12. E. Mathiowitz, J. Jacob, K. Pekarek and D. Chickering, "Morphological characterization of bioerodible polymers. 3. Characterization of the erosion and intact zones in polyanhydrides using scanning electron microscopy," Macromolecules, 26, 6756-6765, 1994.

11. E. Mathiowitz, M. Kreitz and K. Pekarek. "Morphological characterization of bioerodible polymers. 2. Characterization of polyanhydrides by FTIR," Macromolecules, 26, 6749-6755, 1994.

10. E. Edelman, E. Mathiowitz, R. Langer and M. Klagsbrum, "Controlled and modulated release of fibroblast growth factor," Biomaterials, 12, 619-626, 1991.

9. Staubli, E. Mathiowitz and R. Langer, "Sequence distribution and its effect on glass transition temperatures of poly(anhydride-co-imides) containing asymmetric monomers," Macromolecules, 24, 2291-2298, 1991.

7. E. Ron, E. Mathiowitz, G. Mathiowitz and R. Langer," NMR characterization of erodible copolymers." Macromolecules, 24, 2278-2282, 1991.

8. Staubli, E. Mathiowitz and R. Langer, "Characterization of hydrolytically degradable amino acid-containing poly(anhydride-co-imides)," Macromolecules, 24, 2283-2290, 1991.

6. E. Mathiowitz, E. Ron, G. Mathiowitz and R. Langer, "Morphological characterization of bioerodible polymers. I. Crystallinity of polyanhydride copolymers." Macromolecules. 23, 3212-3218, 1990.

5. E. Mathiowitz and M.D. Cohen, "Polyamide microcapsules for controlled release, V. Photochemical release," Journal of Membrane Science, 40, 67-86 (1989).

4. E. Mathiowitz and M.D. Cohen, "Polyamide microcapsules for controlled release, IV. Effects of swelling," Journal of Membrane Science, 40, 55-65 (1989).

3. E. Mathiowitz and M.D. Cohen, "Polyamide microcapsules for controlled release, III. Spontaneous release of azobenzene," Journal of Membrane Science, Vol. 40, 43-54. (1989).

2. E. Mathiowitz and M.D. Cohen, "Polyamide microcapsules for controlled release, II. Release characteristics of the microcapsules," Journal of Membrane Science, 40, 27-41 (1989).

1. E. Mathiowitz and M.D. Cohen, "Polyamide microcapsules for controlled release, I. Characterization of the membranes," Journal of Membrane Science, 40, 1-26 (1989).

21. K. Pekarek Leach, and E. Mathiowitz," Degradation of Double-walled Polymer Microspheres of PLLA and P(CPP:SA) 20:80.I.In vitro Degradation", Biomaterials, 19, 1973-1980, 1998

Jaklenec A, Mallet, V, Fu K, Lotan N, Langer R. Heparin - poly(lactic acid-co-glycolic acid) hybrid: a multifunctional biomaterial. J Biomed Mater Res, Part A..

Background

Education and Training

Year	Degree	Institution
1985	PhD	Weizmann Institute of Science
1979	MSc	Weizmann Institute of Science
1973	BSc	Tel Aviv University

Honors and Awards

2000 The Eurand Award for Excellence in Research in the Area of Oral Drug Delivery Systems.

1994 Recognition Award for Excellence in Guiding Graduate Student Research. Controlled Release SocietyProcter & Gamble. Awarded in Nice, France.

1991-1993 Whitaker Foundation Award.

1985-1987 Bantrell Postdoctoral Fellowship (MIT). A competitive award at MIT in the field of surface science.

1979-1984 Feinberg Fellowship, Weizmann Institute of Science, Israel. A competitive award conferred for graduate research students.

1982 Delek Prize for distinctive research work (Weizmann Institute of Science, Israel).

1973 Distinction Prize for B.Sc. students (Tel Aviv University, Israel).

Researchers@Brown