BB&T Contributing Editor

NEW BRUNSWICK, New Jersey – The New Jersey Center for Biomaterials at Rutgers University (New Brunswick), headed by Professor Joachim Kohn, uses a network of academic, industrial, military and government researchers to foster both basic and translational research aimed at developing the next generation of biomaterials.

The center's comprehensive program is built around five major strategic goals:

• Research excellence.

• Education & workforce development.

• Partnership with industry.

• Advancement of new technologies toward commercialization.

• Fostering entrepreneurship.

At the center's 9th annual New Jersey Symposium on Biomaterials Science and Regenerative Medicine, held here in late October, Kohn described his combinatorial-computational method (CCM) for accelerating the discovery of new bio-erodible polymer technologies and for selecting the optimum biomaterial for use in medical devices. The CCM uses parallel synthesis of polymer libraries, rapid screening and characterization, and computational modeling of cell-biomaterial interactions to identify promising lead polymers for use in the design of medical implants.

Several research projects that were conducted in collaboration with New Jersey Center for Biomaterials have resulted in FDA-cleared products, while others are advancing through the development cycle.

Examples of products that use biomaterials developed in this program are a drug-eluting hernia device for TyRx Pharma (Monmouth Junction, New Jersey) that is fabricated from tyrosine-derived polyarylate, a radioopaque and fully resorbable coronary stent fabricated from tyrosine polycarbonate that was developed for REVA Medical (San Diego) and in clinical trials in Brazil and Germany, and an implantable drug delivery system for ophthalmic use, under development for Lux Biosciences (Jersey City, New Jersey).

Developments in regenerative medicine

One of the key themes of the conference was for accelerating the bench-to-bedside trajectory of regenerative therapeutics. Diverse medical and scientific disciplines are converging toward the reality of advanced regenerative medicine therapies.

These new approaches create living, functional tissues designed to repair or replace tissues or organ function that have been lost as a result of age, disease or injury. Regenerative medicine holds great promise for solving the shortage of organs available for donation.

Dr. Anthony Atala, director of the Wake Forest Institute of Regenerative Medicine (Winston-Salem, North Carolina), reviewed the merged capabilities of regenerative medicine and tissue engineering in applying the principles of cell transplantation, material science and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. Therapeutic cloning and other sources of stem cells, such as those derived from amniotic fluid and the placenta, offer a potentially limitless supply of cells for tissue engineering applications.

Dr. George Muschler of the department of biomedical engineering at the Cleveland Clinic conducts research on bone tissue engineering. All tissue engineering efforts are based on cell therapy. He listed the following four basic cell therapy strategies:

1) Local targeting of cells in native tissues.

2) Homing of cells to a site via systemic circulation.

3) Physical processing and transplantation of cells into a site.

4) biological modification ex vivo prior to transplantation.

Each of these can be used alone or in combination. The most readily available clinical source of stem cells and progenitors are autogenous cells that are resident tissues of the individual being treated.

Alfred Vasconcellos, president/CEO of InCytu Therapeutics (Lincoln, Rhode Island), reviewed the company's use of cell therapy in the development of tissue regenerative products for the restoration of healthy muscle tissues, blood vessels and skin.

InCytu's platform technology, the Cellarium system, was first developed by Professor David Mooney at Harvard University (Cambridge, Massachusetts). It is used to harness biomaterials, cells and bioactive factors for the repair and regeneration of damaged tissues and organs. Products for the treatment of non-healing ischemic wounds and the repair of damaged muscle are under development.

In April 2008, InCytu entered into a partnership with the newly formed Armed Forces Institute of Regenerative Medicine (AFIRM) in hopes of combining their technologies. AFIRM, an exhibitor at the conference, was created by the Department of Defense to focus on research in regenerative medicine.

AFIRM is a virtual organization that includes more than 20 academic and commercial entities committed to developing clinical therapies and advanced treatment options to decrease the time needed for the nation's wounded warriors to recover from severe injuries.

A session on the future of regenerative medicine was chaired by retired Col. Jeffrey Hollinger, professor and director of the Bone Tissue Engineering Center at Carnegie Mellon University (Pittsburgh) and a member of the AFIRM team. He noted that "InCytu plays an important role in the interdisciplinary structure of the Institute, whose goal is to combine world class academia with seasoned, product-oriented expertise."

Dr. Adam Katz, associate professor of plastic surgery at the University of Virginia (Charlottesville), reviewed the benefits of adipose stem/stromal cells which possess similar biological properties and therapeutic potentials as other adult tissue-derived stem cells, but have relative advantages of accessibility, abundance, expendability and donor appeal. Research is ongoing for the use of these cells for cutaneous wound healing.

Product development programs

Professor Doyle Knight of the Center for Computational Design within the Department of Mechanical Engineering at Rutgers reviewed the use of computational modeling of drug delivery by degradable biomaterials. This growing field helps to define how drugs bind to polymers.

The design requirements for degradable biomaterials vary significantly, depending upon the particular therapy, and include the binding efficiency of the drug to the polymer and release profile of the drug as a function of time. The wide variety of potential polymeric biomaterial carriers and the increasingly broad spectrum of drugs has resulted in a combinatorial set of possible drug/carrier combinations that is far too large to evaluate by experiment alone.

A variety of computational models were developed over the past two decades to predict the complex physiological processes including drug binding, polymer degradation and erosion and drug release. They can be classified into three broad categories: empirical, continuum and stochastic. Examples of each were presented and their capabilities and limitations described.

The New Jersey Center for Biomaterials has grown into a nationally recognized resource in biomaterials and has attracted a growing list of industrial members that range from emerging growth companies to major corporations.

BioCure (Norcross, Georgia) reviewed the development of its GelSpray hydrogel for a highly conformable wound packing. The product is applied from a two-component syringe which contains aqueous solutions of polyvinyl alcohol and a polymerization initiator.

The product was evaluated against the Tielle dressing from Johnson & Johnson (New Brunswick) and found to have a higher adhesion to intact skin. An antimicrobial GelSpray containing silver salt showed a 6.5 log reduction compared to a gauze control.

The GelSpray was initially developed for battlefield applications in concert with the Center for Military Biomaterials Research (CeMBR) within the New Jersey Center for Biomaterials, but it also has applications for civilian use. CeMBR was created to become a scientific resource for the military in the field of biomaterials science and engineering.

BioCure is investigated use of the GelSpray system as a platform for the addition of active ingredients to address wound healing, pain, infection and bleeding. GelSpray has FDA clearance for cuts and scrapes, but approval for broader usage is being sought.

The company had previously licensed to Biocompatibles (Farnham, UK) its LiquiGel, an in situ polymerizing formulation for use in embolotherapy. It is delivered from a microcatheter that keeps separate the two pre-polymer components at the distal tip

Lux Biosciences is developing a series of drugs for ophthalmic indications. These drugs are cyclosporin A and voclosporin. The latter drug is a calcineurin inhibitor that is in the development stage and was licensed from Isotechnika (Edmonton, Alberta), where it is being evaluated for treating psoriasis and as an immunosuppressive agent.

LX201 is a candidate for a Phase III clinical trial for use in preventing corneal allograft rejection. It contains cyclosporine in a non-erodible, silicone matrix that is implanted episclerally in the eye and releases the drug over a one-year period.

LX214 is a clear, mixed micellar, aqueous liquid formulation containing volcosporin that is in late pre-clinical development for topical use as an eye drop for the treatment of keratoconjunctivitis sicca.

Drug-delivery systems

Professor Kathryn Uhrich from the department of chemistry and chemical biology at Rutgers presented her research on biodegradable polyanhydrides for use in medical, cosmetic and food applications. The degradation rate of the polyanhydrides can be tailored by changing their chemical composition, specifically, by altering the structure of the linker molecule.

A primary focus of this work is on PolyAspirin, which is a poly(anhydride-ester) that hydrolytically degrades in the body to release salicylic acid in a controlled fashion. By varying the aliphatic, aromatic and branched linkers, degradation rates can be made to vary from weeks to months. High drug loading can be achieved by chemically incorporating the drug into the polymer backbone, and not as an appended group. The range of drugs that have been incorporated into the polymer backbone includes NSAIDs, antiseptics, antibiotics and opiates.

Salicylic acid-based poly(anhydride esters) have been shown to be effective in controlling inflammation, promoting bone growth and preventing biofilm formation. The slow release of salicylic acid helps prevent against restenosis. The polyanhydride polymers have been licensed to Bioabsorbable Therapeutics (Menlo Park, California) for use in their cardiac stent, and to Cappella (San Francisco) for use as a coating on its Sideguard ostium protection device, a self-expanding coronary drug-eluting stent that is first deployed into the sidebranch.

Dr. Avudaiappan Maran, an assistant professor of orthopedics at the Mayo Clinic (Rochester, Minnesota), reported on the use of a novel biomaterial, oligo (polyethylene glycol) fumarate (OPF) hydrogel, for use in the localized and sustained delivery of the anti-tumor agent, 2-methoxyestradiol, for the treatment of osteosarcoma, the most common bone malignancy that primarily affects children and young adults.

The drug was encapsulated into the OPF hydrogel by UV crosslinking and sustained osteosarcoma cell killing was achieved for 15 days.

Nanoparticles for drug delivery

Drug delivery is expected to benefit from the unique ability of nanoparticles to selectively target different tissues and cellular compartments. Nanoparticles can improve the delivery of peptides by rendering them more stable, less susceptible to degradation and able to cross physical barriers that typically restrict circulatory system access.

Professor Larisa Sheihet from the department of chemistry and chemical biology at Rutgers described her work, conducted in collaboration with researchers from the School of Pharmacy, on the use of tyrosine-derived nanospheres for the delivery of lipophilic therapeutics. The majority of drugs, including anti-tumor agents, anti-depressants and statins, are lipophilic and require a solubilization process to enable their parenteral delivery.

The researchers used a biodegradable polymeric architecture with a high degree of structural versatility for the self-assembly into nanospheres of 50 nm diameter. An ABA-type amphiphilic triblock copolymer was derived from natural metabolites. The A-blocks are polyethylene glycol and the hydrophobic B-blocks are oligomers of desaminotyrosyl-tyrosine alkyl esters and non-toxic diacids. These nanospheres were shown to act as an effective sink for binding a wide range of lipophilic drugs.