BBI Contributing Editor

SORRENTO, Italy – The range of topics covered in the 330 oral presentations and 520 posters at the mid-September annual meeting of the European Society for Biomaterials (London) has expanded from prior years and included tissue engineering, scaffolds, biomimetic and biodegradable materials, drug delivery, nano structures and composites. However, there were only a few company exhibitors at the conference, in contrast to the annual meeting of its U.S. counterpart, the Society for Biomaterials (Mt. Laurel, New Jersey).

One key thread of the meeting at the Hilton Sorrento Palace was that the simple view that a biomaterial should cause no harm is changing to the view that such materials should play a positive role in the healing process. That has led to increased study of biomimetic materials and drug-eluting biomaterials.

Biodegradable implants

Bioretec (Tampere, Finland) was formed by management that came from Bionx Implants, which was renamed Linvatec Biomaterials Ltd. (Tampere, Finland) after its sale in 2003 to Conmed (Utica, New York).

The company’s products are in the development stage and include its Self-Locking SL and Auto-Compression biodegradable fixation devices based on PGA/PLA. Also under development are a bioabsorbable sternotomy closing device for use in thoracic surgery and a spinal arthroplasty (spinal fusion) implant fabricated from bioabsorbable materials.

Presentations were given by Bioretec’s collaborators at the Institute of Biomaterials, Tampere University of Technology, on the incorporation of slow-releasing drugs and an osteoconductive Bioglass in bioabsorbable fracture fixation devices. The drugs being evaluated in these devices are the anti-infective, ciprofloxacin, and the anti-inflammatory, diclofenac.

Inion (Tampere, Finland), Bioretec’s competitor which is located in the same city, also is developing biodegradable medical implants. Its OptimaPlus family of biodegradable and bioactive materials are being used to produce medical im-plants that are designed to actively speed up the bone-healing process.

The key ingredient that is responsible for its bioactivity is NMP (N-methylpyrrolidone), an FDA-approved solvent that is widely used for water insoluble drugs. Inion already markets implantable biodegradable devices such as plates, screws and pins.

Degradable Solutions (Zurich, Switzerland) is a contract developer that uses polylactic acid for molding resorbable tissue fixation implants, such as screws, plates, pins and anchors, for use in maxillofacial surgery and small bone fragment fixation. The company uses pressurized carbon dioxide to produce microporous biodegradable foams.

Calc-i-oss is a pure-phase b-tricalcium phosphate used as a bone defect filler in dentistry and orthopedic surgery and is the company’s only product that is available in the U.S. It is sold by Ultradent (South Jordan, Utah). Calc-i-oss granules also have been coated with a very thin layer of resorbable polylactic acid that protects the granules from bacterial attack and allows for fusion of the granules into a solid implant.

The first composite that employs this technology is RootReplica for use after tooth extraction. Degradable Solutions expects to obtain a CE mark by the end of 2005 for Easy-graft, an injectable bone graft which hardens in situ to create a porous, mechanically stable implant that is gradually replaced by natural bone. A strategic partner is sought for this product. Work is under way on implants that release an antibiotic or bone growth factor.

Plasma Biotal (Tideswell, UK) displayed its line of tricalcium orthophosphates which resorb in three to six months. It is used to make composites by adding an ingredient, then pressing and sintering into a shaped material. It is combined with polylactic acid to produce resorbable bone screws. It is used for grafting by Smith & Nephew Orthopaedics (Memphis, Tennessee) and Wright Medical Technology (Arlington, Tennessee).

Drug delivery and cellular therapy

Biocompatibles (Farnham, England), a developer of embolotherapy products for treating uterine fibroids, reported on the controlled release of doxorubicin from microspheres of non-degradable polyvinyl alcohol for use in chemoembolization of hypervascular tumors such as hepatocellular carcinoma. This procedure occludes a blood vessel in order to stop the flow of blood that feeds a tumor.

Researchers from Biocompatibles and the Biomedical Research Group at Brighton University (Brighton, UK) reported on the use of a phosphorylcholine-based gel to encapsulate pancreatic islet cells for transplantation and treatment of Type 1 diabetes. Islet encapsulation in a gel matrix is believed to provide immunoprotection while simultaneously allowing glucose-stimulated insulin secretion to occur.

Hemoteq (Wurselen, Germany) specializes in drug-releasing coating technology for medical devices. The biocompatible polymer coatings can be adjusted to release a drug according to a preset elution profile. Hemoteq’s coating solutions employ a biomimetic nanocoating (Camouflage) and a nanothin synthetic basecoat that resembles the outermost layer of living cells. Its two polymer platforms are Repulsion (biodegradable) and ProTeqtor (biostable). Hemoteq’s paclitaxel-eluting, non-polymer-based drug coating, PacliTeq, received the CE mark in July.

Gene delivery

Successful gene therapy depends on the efficiency of gene transfer and the subsequent level and duration of expression of the therapeutic gene. Several papers focused on enhancing gene delivery. A group from the National University of Ireland (Galway, Ireland) is investigating the use of a fibrin scaffold for overcoming the transient nature of viral vector based gene delivery. The scaffold mimics the final stages of blood coagulation, forming a stable, physiological clot.

Researchers from Ghent University (Ghent, Belgium) reported on their use of a terplex-based non-viral gene delivery system which was composed of a cationic polymer, DNA and the cationic peptide Penetratin. This transfection system opens new perspectives in the field of non-viral gene therapy.

Collaborating scientists from the Swiss Federal Institute of Technology (Lausanne, Switzerland) and the University of California, Los Angeles focused on the synthesis and characterization of a delivery system for siRNA that self-assembles based on charge and hydrophilic/hydrophobic interactions. A specific application that was mentioned is for preventing adhesion formation after abdominopelvic surgery.

Chitosan

NovaMatrix (Oslo, Norway), a unit of FMC BioPolymer (Philadelphia), exhibited its ultrapure Protosan chitosans, Pronova alginates and sodium hyaluronates, which are used in diverse medical applications, including wound-care products, drug-delivery systems, tissue-engineering scaffolds, dermal fillers, device coatings and for cell encapsulation.

Alginate foams and gels can be formulated into biodegradable and non-degradable formats. Alginate is commonly used as an encapsulant for cell-based therapies. Chitosan as a drug-delivery vehicle for morphine is in a Phase III trial by a U.S. pharmaceutical company. NovaMatrix plans to introduce a low molecular weight and specially modified chitosan for delivering genes into cells.

Other commercial sources for medical-grade chitosan are Carmeda (Uppland Vasby, Sweden) and Genis (Sigluffjorrdur, Iceland).

Kytogenix (Chatham, N ew Jersey) is investigating the use of chitosan for drug-delivery applications and is in clinical trials with a chitosan membrane for use as a post-surgical anti-adhesion barrier.

Biosyntech, (Laval, Quebec) is evaluating its chitosan-based BST-Gel for drug delivery applications as well as a cartilage substitute and for wound care.

Biomedical applications of chitosan have been sought for several decades and continue to be the subject of research, as evidenced by the large number of papers on chitosan that were presented at the conference. However, few commercial products have resulted from these efforts. One example is its use in a hemostatic wound bandage sold to the military by HemCon (Portland, Oregon).

Researchers from 3B’s Research Group – Biomaterials, Biodegradables and Biomimetics at the University of Minho (Braga, Portugal) reported on their studies using poly(N-isopropylacrylamide) (PNIPA) in a surface grafted chitosan membrane as a new substrate for cell sheet manipulation and on the endothelialization of chitosan/starch scaffolds for bone tissue engineering. This group has also investigated a scaffold made from chitosan/poly(butylene succinate) that is seeded with mouse mesenchymal stem cells for cartilage tissue engineering.

Novel scaffolds

The potential of biomimetic nanocomposites comprising hydroxyapatite nanocrystals and gelatin in a 3-D scaffold for bone regeneration was found by researchers from Seoul National University (Seoul, Korea) to exhibit an excellent osteoblastic cellular response.

Collaborators from the National University of Singapore (Singapore) and the Hebrew University (Jerusalem, Israel) reported their research on biodegradable elastomers for use in highly flexible tissue scaffolds fabricated via a rapid prototyping technique. The scaffolds were comprised of a copolymer of semi-crystalline poly(e-caprolactone) and poly(ethylene glycol).

The release of the growth factor, TGF-beta1 from a porous polymeric scaffold for cartilage tissue engineering was explored by scientists at OctoPlus (Leiden, the Netherlands) and the University of Twente (Enschede, the Netherlands). The scaffold was prepared from poly(ether-ester) multiblock copolymers. The ability of the TGF-beta1 releasing scaffold to induce cartilage was confirmed in an in vivo evaluation in a rabbit model.

A synthetic self-setting hydrogel scaffold consisting of a reticulated hydrogel of silanized hydroxypropylmethyl cellulose and cultured with chondrocytes was investigated by researchers at University Hospital (Nantes, France) for potential application in cartilage engineering.

Ars Arthro (Esslingen, Germany) has developed a biologically pure and stable matrix for cell cultivation and implantation. Its first product, CaReS, is used for autologous cartilage regeneration. Commercial rights to this technology were licensed by the company from Frauenhofer Institute (Stuttgart, Germany). In July, Ars Arthro received approval from the FDA of its IND application for the clinical testing of its cartilage regeneration technology. The company says that more than 200 patients in Europe have been successfully treated with CaReS.

Collagen and hyaluronic

FibroGen (South San Francisco, California) has developed recombinant Type 3 collagen that has been safety tested in Finland and has been filed for investigational device exemption status with the FDA. A clinical efficacy trial for its use in treating wrinkles is planned to be initiated later this year in San Francisco.

Fidia Advanced Biopolymers, a unit of Fidia Farmaceutici (Abano Terme, Italy), sells a line of hyaluronic acid–based products for tissue repair applications including as a scaffold and for wound care. The company provides in Europe a service of growing autologous tissue from a biopsied specimen submitted by a physician and creating its Laserskin autograft. Its Hyalograft 3D is sold in Italy as a substitute epidermis.

In the U.S., ConvaTec (Skillman, New Jersey), a subsidiary of Bristol-Myers Squibb (New York), sells Fidia’s Epifil for reconstruction of the tympanic membrane, and Epidisk, a stent implanted in the nose. A researcher from Fidia presented a paper on HYAFF120, a UV-polymerized hyaluronic acid-based injectable hydrogel that can be sterilized in aqueous solution for potential use in tissue regeneration and defect filling.

Surface treatments for prostheses

NanoSurfaces (Bologna, Italy), a spin-off company that is owned by Politecnico di Milano (Milan, Italy), has developed BioSpark, a biomimetic treatment of titanium that provides durable osteointegration and antibacterial properties by forming a thin titanium dioxide layer on the surface of the implant. This service is provided by Samo (Bologna, Italy) for treating dental implants.

TiHard is a thick surface coating of titanium oxide that provides low wear, extended life and hydrophobicity for automotive applications, but is being explored for possible use on orthopedic screws, plates and nails to prevent osteointegration and enable removal after implantation.

NanoSurfaces also has developed BioRough, a low-temperature, double-etching process for titanium, first with alkali and then with acid, to yield a surface that affords faster bone ingrowth. This service is provided by Bermedica (Milan, Italy) and is used by IDI Evolution (Biassno, Italty).

TiCare is an anodic polarization with high-temperature thermal treatment that is applied to titanium alloy orthopedic prostheses and titanium dental implants to reduce bacterial adhesion. It was reported by researchers from Polytechnico di Milano and the University of Pavia (Pavia, Italy) not to impair titanium’s biological performance and to promote antibacterial activity against streptococcal strains.

Suriasis (Geneva, Switzerland), a spin-off from the University of Geneva, develops advanced chemical surface treatments for orthopedic implants. Its SurfLink technology is used to covalently immobilize bone onto an implant, resulting in improved fixation, faster healing and increased long-term stability. The SurfLink process is available for license to implant manufacturers.

Valor Medical (San Diego) is developing a new derivative of a cyanoacrylate monomer that polymerizes upon contact with blood for potential use in occluding vascular leaks and as a filler for cerebral aneurysms.

(Included in this report were some biomaterial companies that presented at the Investment in Innovation conference in Brussels, Belgium, that was sponsored by the MedTech Insight subsidiary of Windhover Information [Norwalk, Connecticut].)