Jerusalem Report 2010

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ABOUT 11 YEARS AGO,Meital Zilberman, was at a

career turning point, with a

chance to determine the futuredirection of her work. A fresh

PhD graduate in Materials Engineering in

polymers from the Technion Israel Instituteof Technology in Haifa, after completing her

B.Sc. cum laude in Chemical Engineering andMSc in Materials Engineering at the sameinstitution, she could have chosen to pursue

research in pure materials engineering. But Ifelt that I should direct my efforts to solving

problems for helping people, she says. I

wanted to see the effects of what I did, makinga difference.

Zilberman, 41, now a tenured Associate

Professor at the Department of Biomedical

Engineering of Tel Aviv University, is veryclose to seeing that goal met. Building on bothher extensive understanding of polymers, along

with the experience she gained during a nearlythree-year post-doc at the Biomedical

Engineering Department of the University ofTexas Southwestern Medical Center at Dallas,

Zilberman has carved out a unique specialty inthe creation of biodegradable scaffolds andplatforms that can be implanted in bodies, pro-

grammed to release drugs at the precise places

and times they are needed and then dissolveaway.These polymer-based devices are flexible

enough to serve as the basis for a wide array of

procedures, including: stent implants that spon-taneously disappear after they are no longer

needed, without surgical intervention; wounddressings that are also active dispensers of

antibiotics and that need not be changed; can-cer-fighting fibers that target specific areas of

the body without harming surrounding tissue;periodontal treatment; hernia meshes; and bone

regeneration.For her work, Zilberman was awarded the

prestigious Juludan prize by the Technion in2007, for outstanding scientific researchachievements that shows promise of having

valuable technological applications and arechanneled to enhance mans welfare and pro-

long human life. With her patented inventionssuccessfully passing tests on animals with fly-

ing colors, Zilberman is seeking potential part-ners for commercializing them for human clin-ical use. I always believed that a strong and

THE JERUSALEM REPORT MARCH 15, 2010 31

BUSINESS

The Laboratory of

Medical Wonders

Ziv Hellman

A Tel Aviv laboratory is developing biodegradableimplants that can be used for everything from heartstents to bone regeneration to periodontal surgery

BIOMED TEAM: Prof. Meital

Zilberman, in a red shirt standing

in the back row, with her team at

the Department of Biomedical

Engineering at Tel Aviv University

COURTESY

PROF.MEITALZILBERMAN


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THE JERUSALEM REPORT MARCH 15, 201032

BUSINESS

solid scientific basis needs to precede commer-cialization, she says. Now that the scientific

basis has been attained, after several years ofintensive work, we can start working towards

commercial applications.

ZILBERMAN RECALLS THAT

during her childhood, in Haifa, she wasalways drawn to science, but it was

during the formative post-doc at the Universityof Texas that she first came into close and

intensive contact with biomedical engineering,when working with Prof. Robert Eberhart, one

of the U.S. pioneers in the field. Her research inDallas focused on stents for coronary, tracheal

and urethral applications.When she returned to Israel, in April 2002,

to establish her own laboratory at Tel AvivUniversity in biomaterials and tissue engineer-ing, the basic outlines of the labs focus were

mapped out: polymeric biomaterials, active

implants, controlled drug and protein release,and scaffolding for tissue engineering. She cur-rently conducts a research group of 10 graduate

students studying towards PhD or MSc degreesin biomedical engineering or materials science

and nanotechnology, working in her lab in theuniversitys multidisciplinary building, whichis filled with advanced high-tech machinery for

measuring the molecular properties of poly-mers.

Coronary stents are typically implanted sur-gically to keep blood vessels open after angio-

plasty has identified the site of a blockage. By

preventing the collapse of weakened arteries,they can be lifesavers. But most cardiologistsfind that stents are not needed for longer thansix months, after arteries have regained

strength.Biodegradable polymers offer a solution.

Polymers are macromolecules comprised ofrepeating structural units connected by chemi-

cal bonds, used in an immense number ofindustrial products. In many cases, chemical

engineers struggle to prevent polymer degrada-tion, which occurs when environmental factors

cause hydrolysis of the bonds connecting thepolymer chain. If not stopped, polymer degra-

dation can so reduce the molecular mass of thepolymer that full dissolution ensues.

Zilberman explains that polymer degrada-

tion can be a positive aspect when it comes tostents. With her understanding of the chemical

properties of polymers, Zilberman can pro-gram the timing of polymer degradation,

while at the same time creating a polymer-based stent that has sufficient strength to serveas efficiently as a metal stent for the sustained

opening of arteries. When time is up, and thestent is no longer needed, it simply dissolves

away, requiring no effort at all. The end prod-uct is just water and carbon dioxide, notes

Zilberman, which is non-toxic, and simplyexcreted by the body.

But the wonders of polymer stents do not

end there. Medical doctors have long recog-nized that stents can be used to do more than just prop up conduits in the body; given thatthey are implanted in the body, why not use

them to release drugs locally, at their implanta-tion sites? Drug-eluting stents were designed to

do just that, releasing antiproliferative drugs,immunosuppressants, or growth factors.

The problem with standard drug-elutingstents, however, is that coating manufacturers

have been unable to develop a method forreleasing them in a controlled manner, accord-

ing to Zilberman. Insolubility in water is usual-ly the hurdle that coating manufacturers have

run into.But Zilberman discovered that a coating

made from the porous structures of polymers isperfect for drug diffusion. By controlling the

chemical properties of the polymer fibers,Zilbermans patented inventions enable doctors

to specify a desired drug release profile that isbuilt in to the stent. The polymer stent itself

then releases the appropriate doses of thedrugs, at pre-determined time intervals, until it

dissolves away.There are some cardiologists, however,

who would prefer to leave stents in place,notes Zilberman. But that does not mean thatthe drug-eluting properties of the polymers

cannot be used by them metal stents can alsobe coated by our novel coating, enabling them

to release drugs under prevision release pro-files, without the dissolution. Zilbermans

PhD student Amir Kraitzer worked on this pro-ject with her.

IN HER OFFICE AT TEL AVIVUniversity, Zilberman pulls out a small,

square sample of a wound dressing thatJonathan Elsner, another of her PhD students,

has been creating. To the naked eye, it lookslike a standard piece of gauze, as might be

found at any nurses station. But it could revo-

lutionize the treatment of burn victims.Despite the advances in treatment regimensand the efforts of doctors and nurses, some 70percent of victims of severe burns die not from

the burns themselves, but from related infec-tions. The true danger faced by those who

have suffered skin burn is that they no longerhave the barrier of healthy skin to keep out

infections, says Zilberman. People who suf-fer from large burns dont usually die from the

condition itself. The fatal culprits are the sec-ondary bacterial infections that invade the bodythrough these vulnerable burned areas.

Antibiotics, of course, are the tool used to

fight infections, but for burn victims, it ispreferable to use locally-applied antibiotics, inorder to target and kill harmful bacteria before

they enter the body to cause further infection,sepsis, or death. Adrug-eluting wound dressing

that can regularly release antibiotics in place istherefore exactly what is needed. Couple thatwith the fact that a wound dressing is eventual-

ly unneeded, but painful to remove and itbecomes clear that a polymer fiber-based

wound dressing that both releases drugs anddissolves itself should find a large potential

market, and that is exactly what Zilberman has

developed. According to a study published byher, the new dressing can eradicate infection-causing bacteria within two days, and continue

to do so for as long as needed, again using thecontrolled release profiles programmed into thepolymers.

We can also incorporate growth factorsand pain relief medication into the dressing

itself, so that these do not need to be adminis-tered separately, says Zilberman. Wound

cleaning and redressing is avoided, as are toxi-city issues that can arise when the same amount

of antibiotic passes through the body [insteadof being applied directly on the site]. The

dressing is usually programmed to releaseantibiotics and other drugs for three to fourweeks before totally degrading.

The new wound dressing has been designedto mimic the mechanical and physical proper-

ties of skin in many ways. To do so, it needs tomaintain a certain level of moisture, while at

the same time acting as a shield against infec-tions. The dressing also enables fluids from thewound to leave the infected tissue at a certain

By controlling the

chemical properties of

the polymer, Zilbermans

inventions enable doctors

to specify a desired

drug-release profile


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THE JERUSALEM REPORT MARCH 15, 2010 33

rate that has to be timed just right. If too fast,the wound will dry out and it wont heal

properly. If too slow, theres a risk of increasedcontamination.

The polymer-based wound dressing looksand feels like standard dressing material and is

administered by medical workers normally. It

can serve as a self-dissolving dressing for anypurpose, not just for treating burn victims, and

those suffering from major wounds, bed sores,or diabetic ulcers can benefit from it as well.

Tests of the dressing being conducted on ani-mals, in a project conducted in collaboration

with Prof. Yehuda Ullmann, head of RambamMedical Centers Plastic Surgery Department

in Haifa, and co-project leader, Prof. IsraelaBerdicevsky of the Technions Faculty ofMedicine, have returned excellent results.

ALONGSIDE THE SAMPLE

wound dressing, Zilberman pulls out

a sample that is even smaller ofthreads. Adressing is woven from threads, andthose individual threads, constructed of drug-

eluding and self-dissolving polymers, are per-fect for use as surgical sutures.

One potentially lifesaving use of the fibers

is in cancer treatment. Releasing cancer-fight-ing drugs the fibers can give doctors the oppor-

tunity to be very precise in the cancer cells theyare targeting. Zilberman foresees an immediate

application in the treatment of cancers locatedin hard to reach or sensitive areas, such as brain

tumors, where one wishes to avoid removing

any of the tissue surrounding the tumor itself.By implanting the sutures in the right place,they can be focused on the tumor, not healthybrain cells. Given how thin and delicate they

are, they can be inserted into the body usinglaparoscopic methods, further increasing

chances for a full recovery.Zilbermans experiments indicate that indi-

vidual polymer thread sutures can be pro-grammed to keep releasing drugs for nearly an

entire year. When you remove a tumor fromthe brain, you dont want to touch the sur-rounding brain tissue attempts to do so may

lead to additional tissue damage, she says.

But if you leave our biodegradable drug-loaded fiber in the brain, it could do the work,then disappear when its no longer needed. The

project is being conducted in collaborationwith Prof. Yoel Kloog, the dean of Tel Aviv

Universitys Life Sciences Faculty.Additional uses immediately envisioned for

the sutures is for periodontal treatment, where

the sutures can be introduced to dental pocketsfor antibiotic release, and as a mesh for hernia

repair. Given the flexibility inherent in thethreads, there will doubtless be many more

applications that will be imagined.

POLYMERS CAN BE FLEXIBLEenough to form threads, but also suffi-

ciently rigid to serve as scaffolds for

hard tissues. This suggests that they can beused to aid the body in tissue regeneration.

Polymer-based scaffolds have the potential tobe used in tissue engineering to replace a wide

range of damaged tissue, says Zilberman.That can include skin, bone [such as after

tumor removal], nerves, muscles, blood ves-sels. Polymer structures are appropriate as the

material for scaffolds because they can be bothporous to enable cell growth and releasegrowth factors and strong. And of course, we

want the scaffold to dissolve away when it is nolonger needed to guide tissue growth.

That bone regenerates naturally under theright conditions has been known for ages and,

in effect, is the basis for setting limbs in casts totreat broken bones. But when pathology, trau-

ma, or surgery has caused too much bone mate-rial to be lost, it is often lost forever. The idea

behind guided bone regeneration is to providethe body with a scaffold that coaxes and guides

bone growth in the right place and amounts toenable lost bone material to be replaced. Thiscan be tricky, because bone is a composite

material, consisting of both aqueous aspects

that enable it to resist tension elastically, and amineral component for resisting compression,while at the same time serving as a medium for

diffusion of biologically active agents.Scaffolds need to be strong enough to main-

tain mechanical function while they exist,while being porous enough to enable diffusion and to be easily removed when no longer

needed, just like scaffolds around buildings aretaken down when construction is completed.

Self-degrading porous polymer scaffolds,loaded with growth factor molecules and pro-

teins released in a controlled manner over time,are the solution to this need.

As Zilberman explains, the scaffold can beprecisely designed and shaped, in three-dimen-

sions, to shape the growing bone. The porous-

ness of the polymer enables the effective deliv-ery of bioactive agents that spur bone and tis-sue to regenerate to the tissue surrounding themissing bone. It is a delicate balance, she

says. We needed to get the conditions right, interms of being both porous and strong.

The most immediate application, she con-tinues, is likely to be in the oral cavity, to cre-

ate new hard tissue growth for the stableplacement of dental implants. Dental

implants usually involve using of titaniumimplants as dental roots, explains Zilberman.There are people whose bone in the jaws

have degenerated to such an extent that the

bones are insufficiently dense for the titaniumimplants, and must make do with denturesinstead. With regenerated bone material, they

could also have dental implants. The projectis being conducted in collaboration with

Prof.Yitzhak Binderman, TA UniversitysFaculty of Dental Medicine.

Looking forward, Zilberman continues to

work on challenging tissue engineering prob-lems. One area of current research involves the

use of natural, as opposed to artificial poly-mers, for certain implants, especially for use in

medical adhesives, loaded with bio-active

materials, for soft and hard tissues Such adhe-sives need to be bio-compatible, she explains.This means that using natural polymers isimportant for this applications.

The success of her work has not gone unno-ticed. Zilberman has been awarded several

prizes, from the time she was a PhD student inProf. Arnon Siegmanns group at the

Technions Faculty of Materials Engineering.One of them was the prestigious Ministry of

Sciences Eshkol Scholarship. She has pub-lished more than 60 peer-reviewed articles in

the top biomaterials journals, and even servedfor three years as the director of Graduate

Studies at Tel Aviv Universitys BiomedicalEngineering Department.

But the main motivation, for her, has always

been using the basic insights gained after yearsof hard work in the lab in the service of applied

medical treatments. There are researcherswho want to concentrate solely on pure sci-

ence, she says, and that is fine. But, for me, Iwant to see my research make a difference, forpeople.

COATED STENT

COURTESY

PROF.MEITALZILBERMAN

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Jerusalem Report 2010