Biomedical Functional Materials
Popular scientific description
Over the past years scientific advances, especially within cell biology and synthetic polymer materials, open completely new possibilities for advanced implantation surgery where sick and injured organs are replaced with artificial tissue. The need for implants is today much larger than what can be delivered by human donors. A very promising technique for tissue reconstruction is tissue engineering, in which tissue specific cells are grown, in vitro before implantation or in vivo, over a polymeric scaffold that temporary carries the mechanical load after which it is gradually resorbed while the body’s own tissue
The goal of this project is to synthesize resorbable polymeric materials with specific and functional architecture through ring-opening polymerization and new advanced initiator-systems. Interdisciplinary cooperation between polymer technology, biotechnology and medicine create a dynamic scientific milieu, with a broad competence allowing for the possibility to manufacture synthetic analogues to natures hierarchic biomaterials; degradable polymers with well-defined structure and properties tailor-made to fore fill all demands placed on synthetic implants in real, biomedical applications.
These new materials are made with a number of applications within tissue engineering and drug delivery in mind. Resorbable networks that are appropriate for replacing soft tissue, where our polymers unique combination of hydrophilicity and elasticity will be made and these materials cell interactions studied. Copolymers with good mechanical properties and retained flexibility are promising materials for sutures, joints and membranes. Such materials will be made and tested with respect to biocompability along clinical usefulness.
A good interaction between the substrate and the living cells is fundamental within tissue engineering. To stimulate cells adhesion, proliferation and orientation the resorbable polymeric implants with specific surface patterns of nano dimensions will be developed. Furthermore delivery of drugs, e.g. growth factors, from the artificial tissue is an active tool to stimulate the tissue regeneration process.
Several years of synthetic and analytic work will be the foundation for the usage of these materials in varying biomedical applications. It is for the future usage of these materials of outmost importance that the possibilities to further develop the synthetic routes of these materials and to create a large-scale production of the materials considered.
Synthesis of New Resorbable Polymers and Networks Having Different Architectures
The foundation of the entire project is our ability to construct resorbable polymers and networks having different architectures and compositions. Each alteration of the structure provides materials with new characteristics, since the shape and composition of the polymer determines the property profile of the material. Structural features we have created that aid or directly generate variations in the final material include:
• Functionalization of the polymers, either as end-groups or amid the polymer chain. The functional groups can be used in successive polymerisation reactions creating advanced structures such as star shaped polymers, networks, comb or brush like polymers.
• Copolymerization using different monomers; enabling diverse combinations of favourable properties such as hydrophilicity/hydrophobicity, mechanical strength and tailor made degradation characteristic.
• The creation of networks. Hydrogels, that is a polymer network that can absorb and retain water without dissolving, is one of these materials. Varying synthetic routes have been used all striving for good control over the segmental length and thus of the pore size.
The preparation of porous scaffolds. Their function is to serve as an adhesive substrate for cell attachment and in growth as well as physical support, while guiding and aiding the formation of new tissue. To be able to fully investigate the true potential of our materials a large-scale production facility needs to be developed and built. This will be done in collaboration with Dr. Mathisen, Radi Medical Systems.
Biomedically Adapted Surfaces
Whenever a biomedical application of a material is intended, the device surface and the response reaction of the host to a foreign material remaining in the body for an extended period of time are issues of concern. Any polymer to be integrated into such a delicate system as the human body must be biocompatible and the chemistry and topology of the surface must be such that the device will trigger an appropriate host response. The surface of polymers can be modified through many different techniques such as grafting, immobilising bio-molecules or specific functional groups, or nano-patterning. These surface modifications may have an important effect on the biological response, e.g. serve as a guide for cell adhesion and proliferation.
Our polymers possess a strong potential in the field of biomedical materials, in particular as implants of various kinds. To comply with the high prerequisites of biocompatibility, as well as to meet the increasing demands of functional and tailor-made surfaces of the future, much effort in our laboratory is devoted to surface modification, especially toward the design and development of functional and nano-structured surfaces.
As far as functionalization is concerned, we have elaborated several grafting techniques for the synthetic modification of polymer surfaces, typically involving two separate steps. Firstly, the polymer groups exposed on the surface are activated in any of a number of ways,
for example via plasma- or electron beam-irradiation. The activated groups are in a second step allowed to react with any of a number of investigated, desirable species so that new oligomeric or polymeric side groups, i.e. grafts, are covalently attached to the polymer surface. These methods have also been successfully applied to biodegradable polymers. If needed, the graft end groups can be further modified in subsequent steps. By a proper choice of graft chemistry, the substrate surface can be designed to promote or prevent cell growth, stimulate or prevent blood clothing, attract or reject specific proteins, or in some other manner control its biological response.
Nano- or submicron patterning of conventional and biodegradable polymers is made in our laboratory with various techniques, such as demixing, embossing on templates, or patterned surface grafting.
The two latter techniques offer options to provide chemical functionality or bioactivity by subsequent coupling steps. The nano-structured substrates are particularly needed in research devoted to the study of the influence of surface morphology and chemical composition on the adhesion and growth of different types of cells. From an applicability point of view, these structures are able to adequately orient the growth of specific cells in the tri-dimensional space, allowing for the regeneration of specific biological tissues.
Characterization of the Developed Materials and their Degradation
How a polymeric material behaves in the human body depends, among other things, on the interactions between the human body and the degradation products released from the material i.e. their amount and release profile. What degradation products are formed is determined by the chemical structure of the material, while large differences in degradation rate and amount of products released are observed depending on the degradation environment or body location. Despite of many studies, these interactions are still not completely understood and there is a need to systematically study the effect of different parameters on the degradation process.
During the project qualitative and quantitative analysis of the hydrolysis products released during ageing will be performed. Is the material totally degraded to water-soluble products?
Are the products released continuously or in a burst? Is it likely that the acidic degradation products accumulate or will they be removed by body fluids? What is the relationship between structure and release profile? To fully exploit the potential of macromolecular engineering we need to learn more of the structure-property relationships and the interactions between polymers and their environment.
This project has all the necessary tools to increase this knowledge. A systematic study of different polyesters varying in chemical composition, molecular weight, macromolecular architecture, size and shape subjected to different ageing conditions will provide new tools to designing structures for tailor made properties, predetermined degradation rates and controlled release of degradation products. We have long experience in studying degradation of different inert and degradable polymers in biotic and abiotic environments. Several advanced extraction methods have been developed to accurately extract and identify the low molecular weight products migrating from polymers.
We have also shown that the type and amount of degradation products can be correlated to changes in matrix properties like molecular weight and mechanical properties. The knowledge obtained during previous studies will be a valuable help in the designing the test method and in the analysis of release profiles for the synthesized polymers.
Applications in the Field of Tissue Engineering
To facilitate the in vivo culture of tissues as well as guided tissue regeneration, there is a great need for biodegradable matrices. However, the exact specifications for materials used when engineering different tissues is not known, why new candidates have to be tested in vitro and in vivo. By culturing cells from a large number of human tissues we have the ability to study the materials capacity to stimulate cell adhesion, proliferation, migration and synthesis of new tissue, important phases in the regeneration process. After seeding the cells on the matrix, immunohistochemistry as well as routine staining is used to investigate the cell-matrix interactions. The next step
is to integrate promising materials in viable human tissue in vivo. The aim is to closer investigate, in a standardized way, the integration of the matrix in a viable system, which includes all the cells building up the tissue in question. Events such as formation of new tissue and revascularisation will be studied. Finally, a clinical study is initiated based on the in vitro results and preceded by usual safety studies.
Since our polymers are intended for in vivo use, the response reactions of the host to the foreign material is an issue that needs to be addressed. We plan to evaluate the biocompatibility in two stages. Stage I is planned for the second year of this project and involves a pilot study where samples
of interesting polymers are implanted in rats, or animal models of the corresponding size, to generate preliminary data on biocompatibility and host response. A more elaborate study, Stage II, is planned for the fourth year of this project, in which a more extensive series of tests is performed in animal models that more accurately correspond to the tissue response of humans, e.g. sheep or pigs.
There are today a number of different sutures commercially available, permanent as well as degradable. Their relative stiffness is however a common concern and risk impairing the patient compliance. We believe that our copolymers present
a promising alternative to these, since they are comparably softer and flexible.
2. Ligaments such as cruciate ligaments
Orthopedic surgery is often concerned with the repair of torn or otherwise damaged ligaments, especially cruciate ligaments around the knee joint. Conventional surgery involves the implantation of an artificial ligament that will permanently bear the load and hence replace the damaged tissue. An improved approach would be to implant an artificial and degradable ligament, a stent, next to the damaged tissue. This stent would then bear the full load of the ligament for a limited time while gradually degrading, thereby stimulating the damage ligament to regenerate.
The healing process succeeding orthopedic surgery often involves membranes (fersia) extending over e.g. a bone outgrowth. In these cases there is always a risk of the bone and fersia fusing, a problem avoided if a thin membrane covers the outgrowth. Our copolymers present an attractive material choice for these membranes, since they are readily haemocompatible by surface modifications using heparin.