Originally Published November/December 2000
Special Report
Natural Biomaterials Benefit Implants
Industry is partnering with academic researchers to explore the use of natural materials in implantable devices and tissue engineering.
Benjamin Lichtman
Seven groups of researchers are cooperating on a project that may well revolutionize the science of implants. Notable among them are scientists at the University of Minho (Portugal), who are pioneering the use of natural materials such as starch in orthopaedic applications, and the Dutch company IsoTis N.V. (Bilthoven), a firm with expertise in hybrid implants built from engineered tissue scaffolds and living cell cultures. The research of both groups is driven by the belief that scientists should look to nature when designing devices for implantation.
The "3Bs" group at the University of Minho's polymer engineering department earned its moniker for its work in the areas of biomaterials, biodegradables, and biomimetics. The group, codirected by Assistant Professor Rui L. Reis and Associate Professor Antonio M. Cunha, consists of approximately 20 researchers working in the northern Portuguese cities of Braga and Guimarães. Over the past 6 years, the 3Bs group has investigated the potential of starch-based polymers in biomedical applications such as bone replacement and drug delivery. Recent efforts have focussed on the development of new thermoplastic proteins from casein and soy materials in cooperation with the Agrotechnological Research Institute at Wageningen University and Research Centre in the Netherlands.
Mimicking Nature
Reis explains that his research focusses on the potential applications of natural materials in medical implants. According to Reis, starch-based biomaterials offer a range of advantages when compared with synthetic materials, including their ease of processing, degradability, biocompatibility, exhibition of bone-analogous properties, bone bonding, and ability to be surface engineered to produce desired mechanical and biological behaviours. In addition, Reis notes that starch-based materials are significantly less expensive than most commercial synthetics. Applications under investigation for the starch-based polymers include bone replacement and fixation, the filling of bone defects, and the creation of tissue engineering scaffolds, bone cements, and drug delivery carriers.
IsoTis is developing a process in which bone marrow cells are harvested from a patient, cultured on starch-based or synthetic structures, and reimplanted. The above image shows cells developed using this technique in animal trials.
"Many biological structural materials consist of inorganic minerals combined with organic polymers," says Reis, citing oyster shells, coral, ivory, pearls, sea urchin spines, and cuttlefish bone as examples of the cornucopia of materials engineered by living creatures. "The study of these structures has generated a growing awareness in materials science that the adaptation of biological processes may lead to significant advances in the controlled fabrication of superior smart materials," he says. To date, scientists have not succeeded in reproducing the intricate microarchitectures that are generated seemingly effortlessly by nature. This is what the 3Bs group is aiming to achieve by using natural materials and developing biomimetic methodologies.
Reis's group cooperates with several other universities, including Brunel University and the University of Liverpool (both in the UK), CSIC-Madrid (Spain), Twente University (Netherlands), Hacettepe University (Turkey), the National Institute for Advanced Interdisciplinary Research (Tsukuba, Japan), and the National University of Singapore.
The group has received EU funding for two projects in which it partners with private companies. The first is IsoBone, a {6.6-million project investigating tissue engineering for bone replacement. The group is also participating in another European project for a product called Algisorb, a biodegradable bone-forming material of algal origin enriched with bone growth factors.
Achieving Bonelike Properties
Reis and his team seek to develop natural bone replacement materials that have desirable biological characteristics. "We're looking for materials that display mechanical properties analogous to those of bone that then degrade at a rate similar to the rate of bone healing," Reis says, adding that this has never been done with synthetic degradables.
Conventional synthetics used in implants include polylactides, polyglycolides, and polyhydroxybutyrates. But these materials are difficult to make into injection-moulded structures with good mechanical properties because of their sensibility to moisture and temperature. The polymers are easily degraded and often have to be stored under vacuum or at controlled temperatures. Furthermore, Reis notes, it has never been possible to fully replicate the structure of bone using such polymers.
In bone replacement, starch-based materials may also offer a solution to the problem of stress shielding, which often occurs with metallic implants that do not transfer sufficient load to the surrounding natural bone. Starch-based polymers would address this problem by degrading in situ and allowing natural bone to take on load, which is a necessary step in the healing process.
"We always try for nice mechanical properties," says Reis, explaining that his group is seeking to develop a material that can be processed by a melt-based technology, such as injection moulding or extrusion. The 3Bs group processes starch-based materials with an unconventional technique called SCORIM (shear-controlled orientation in injection moulding) to achieve the desired mechanical properties. The technique was developed in the late 1980s at Brunel University and is based on standard injection moulding, with the addition of a device (a so-called SCORIM head) incorporating hydraulic pistons that move at a controlled frequency to pack and shear the melt. "You can get very good morphology with this technique," says Reis, "allowing you to copy the osteonic orientation patterns of bone."
According to Reis, starch-based materials are easy to combine with a bonelike filler material (such as bioactive glass, hydroxylapatite, or another calcium phosphate). "This is of primary importance, because the bioactive filler will not only give rise to a stiffer material, approaching the mechanical performance of bone, but also will ideally confer a bioactive (bone-bonding) nature to the composites. This will prevent the formation of fibrous encapsulation and may lead to an 'ideal' implant-bone interface that will not need to be cemented," he says.
While the development of an effective bone replacement material will eliminate the need for bone cements, Reis and his colleagues are currently developing new starch-based bone cements for use in conventional implants. "Starch takes up water, so it is less aggressive to body tissues," says Reis. "Also, it can be engineered with setting and mechanical properties similar to those of conventional materials, but it is partially biodegradable, allowing bone to grow into it, and achieving a better lock."
Porous calcium phosphate on which osteogenic bone marrow cells were cultured for 7 days, following 6-week subcutaneous implantation in mice. Abundant bone and marrow have been formed.
Because starch materials easily take on water, they are also easier to coat with calcium phosphate layers via biomimetic technologies. This is where IsoTis comes in. The Dutch company—which was formed in 1996 as a privatization of a research group at Leiden University—is coordinating the IsoBone project that the 3Bs group is working on. IsoTis is developing a process in which bone marrow cells are harvested from a patient, multiplied in vitro, shaped in the appropriate structure, and implanted into the patient. The company has achieved a turnaround time of 4 weeks for this process, for which the first clinical trials will start within a year. IsoTis expects to launch fully tissue-engineered bone commercially in 2004.
IsoTis recently achieved a significant milestone in relation to its biomimetic calcium phosphate coating technology. In 1999, the first hip prosthesis coated with the company's biomimetic calcium phosphate layer was placed in a human patient at the Academic Hospital in Maastricht, Netherlands. In the same year, IsoTis received the CE mark for the coating as a medical device.
"The use of living tissue is the key to the future of implant technology," says Joost de Bruijn, senior research scientist at IsoTis B.V. "We want to look at the human body, replicate tissues in vitro, and then implant them into the body." According to de Bruijn, his company's research shows that this approach has more success than implanting inert materials. "The body is dynamic," he says. "Look at bone, which is continuously broken down and built up again. Inert materials cannot participate in the generation of tissue; at best, they might guide bone formation."
De Bruijn notes that the move toward active implants will require a new generation of medical devices that are suitable for interaction with hybrid materials. "I'm expecting big changes in the device industry in the next 10 to 30 years," he says. IsoTis develops tissue-engineered bone for revision surgery, spinal fusion, and dental implants. The company is also developing proprietary hybrid technologies for the replacement of cartilage and skin, and will host a symposium on tissue engineering in Utrecht, Netherlands, on 17 November (see "Industry News: Shows and Conferences," page 23).
Predicting the Body's Response
Clearly, any material that will be implanted in the body must undergo a spate of biocompatibility tests. Reis notes that his group has carried out extensive in vitro and in vivo studies of the starch-based polymers, including in vitro studies and animal trials in conjunction with IsoTis and the University of Liverpool. John Hunt, lecturer in clinical engineering at the University of Liverpool, emphasizes the importance of thorough testing for biomaterials, suggesting that manufacturers should go beyond the ISO standards for biocompatibility. "There's a further due diligence that manufacturers should pursue," he says. "I'm talking about the more specific responses that your device might stimulate. Many of the ISO standards cover things like cytotoxicity, which you must be sure about. But in different applications, your material or device could stimulate a different response. And it's those kinds of situations and special responses that we want to investigate.
The osteogenic bone marrow cells pictured above were cultured for 7 days on a porous hydroxylapatite substrate in a bioreactor.
"Many manufacturers will make a change, see that it's better, and proceed with it, but they don't really know why it's better," adds Hunt. "Almost 5 years down the line, they'll find out why. We're trying to develop the research and the tests that will predict that a small change in your material will enhance a specific cellular response—is that the cellular response that you want?"
To date, test results for Reis's starch-based polymers have been promising. "The materials exhibit nice biological behaviour," says Reis. "The typical problem with biodegradables is that they are designed to leach into the body. For example, polylactides or polyglycolides, which are the gold standard in this area, produce a big pH drop, and can lead to inflammation. With our materials, you get much better biological performance," he says, noting that maltose, fructose, and similar molecules are the typical products of the degradation of starch-based polymers. "This is the same thing your body produces when you eat rice or bread," he says. In addition to conducting the standard cytotoxicity tests on the materials, Reis and his colleagues are investigating the body's immunological response to starch-based polymers.
The Evolution of Biomaterials
"Nature is, and will continue to be, the best materials scientist ever," says Reis, noting that mineralized tissues such as bone, tooth, and shell have always attracted considerable interest as natural anisotropic composite structures with good mechanical properties. "One can define the aim of materials science as the design and processing of materials for optimized performance in a specific function," he states. "Who better than nature to design complex structures and control the intricate processing routes that lead to the final shape of living creatures?" In this light, says Reis, natural mineralized tissues should make good models for the materials scientist of the future.
Straddling the line between theory and application, Reis and his group can already produce bone plates and fixation screws from starch-based materials by injection moulding, and have the aim of producing full implants using the same technology.
"We are looking for a strong strategic alliance with a private company—that is what we really need" says Reis. IsoTis is the likely partner for tissue engineering research, he says, adding that his group is open to new proposals for other areas, including drug delivery, bone replacement and fixation, or biomimetic methodologies. "We already have some experience working with private companies," he says, noting that the research group has formed other partnerships in a variety of industries and that EU funding requires it to partner with industry members. Besides, he says, "as engineers, we're very application oriented by nature."
Stimulating Research
In 1998, Dutch biomedical company IsoTis N.V. (Bilthoven) and six international partners were awarded a {4.1-million grant for the IsoBone Technology Project from the BriteEuRam III Programme for Industrial and Material Technologies, a European Commission–sponsored R&D competition.
IsoTis is the coordinator of the project, which is aimed at developing living tissue-engineered bone substitute materials that can replace load-bearing and non-load-bearing bones affected by disease, trauma, or age. Because the mechanical, chemical, and biological properties of the replacement material will be identical to those of normal human bone, the partners believe it will present significant advantages over current materials such as human and animal grafts, or artificial materials such as metals.
Partners in the IsoBone project include Minho University (Portugal); Britain's Cinpres Ltd. (Tamworth, Staffs), which is focussing on unconventional processing techniques for polymeric matrices; the Italian chemical firm Novamont S.p.A. (Novara), which has experience producing starch-based materials; Brunel University (UK), which will design the polymer matrices; INEB (Portugal), a research institute that will enhance matrix bioactivity; and Twente University (Netherlands), which is specializing in synthetic polymers.
For more information on EU-sponsored research programmes, visit the EU Web site.
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