Design and synthesis of raw materials
The Action aims to develop a network with intensive interactions between new biomaterial designers, industrial producers and users, in order to generate innovative concepts in the field of bone substitutes.
The scientific tasks to be pursued to fulfil this aim are of three kinds:
Biomaterial preparation: Biomaterials can be divided into four major categories: metals, ceramics, polymers and their composites. Indeed, according to expectations, the ideal bone substitute should:
- Be fully biocompatible and available in a variety of forms and sizes
- Present appropriate mechanical properties
- Form a chemical bond at the tissue/implant interface
- Exhibit a network of open porosity
- If biodegradable, showing a kinetics matching the healing rate of human bone tissue with absence of any chemical or biological inflammation caused by release of substances
Regeneration of natural bone, rather than repair, is the central goal of any tissue engineering strategy, and this will vary as a function of the age of the patient, meaning that a given implant for the same maxillofacial or cranial region must be available with various chemical compositions in order to be degraded in concert with in-growth of natural bone tissue. Different bioresorbable materials exist with various degradation rates.
Calcium phosphate bioceramics (CaP) are the main material or filler for bone substitutes as their chemical composition is similar to that of natural bone. The CaP-bone interface is created by the conversion of the dissolved Ca and P ions into a carbonated apatite and subsequent integration with bone tissue. One current problem is that the mechanical properties exhibited by porous CaP materials are lower than those of natural bone. Therefore, ceramics are combined with polymers to mimic the structure of natural bone. Two current strategies exist: (1) the bioceramic scaffold is impregnated by a polymer to improve its energy to failure and to allow drug release; and (2) the use of polymer routes (injection, etc.) to make complex shapes, where the matrix fillers can be ceramics, cements, putties or bioactive glasses. At the same time, the poor bioactivity and local acidity left by degradation products (causing inflammation response) of most polymers can be counteracted: There is a need for biocomposites combining properties of CaP ceramics, bioglasses, metals and polymers.
Expected deliverables: development of biomaterial feedstock with adapted bioresorption rates for absorption tests and for the study of their ability to be shaped by the innovative process like rapid manufacturing techniques.
Design, rapid manufacturing processing and characterisation: Despite the advantages of the composite scaffolds, if the CaP material is too dense and does not present a good pore fraction with appropriate pore sizes, it will have poor degradation properties, delaying the bone in-growth process. The synthetic scaffold should ideally exhibit a hierarchical pore size distribution, ranging from less than 1μm (for bioactivity and interaction with proteins) to more than 500μm (for implant functionality and cellular in-growth). The structure on the nano scale is of relevance as well; especially for the adsorption of proteins. In addition to porosity, a good interconnectivity is also needed for the biomaterial since this allows good transport of body fluids within the scaffold for better cell invasion (100 to 200 μm). In order to achieve this internal structure with graded porosity and chemical compositions, bio-functionally graded composites have to be designed and fabricated. New emergent technologies are available to allow this technical challenge, such as rapid prototyping and manufacturing techniques.
In orthopaedic repair surgery, clinicians must accommodate important additional parameters, to those met in other branches of surgery, such as excellent implant stability and very accurate three dimensional shapes (for example for aesthetic reasons). Rapid prototyping technologies have revolutionized a generation of physical models and allow efficient and accurate production of customized implants with high levels of geometric intricacy: There is a need for functionally graded biomaterials, in terms of internal structures and composition – can be fabricated by development of an innovative multi-material rapid manufacturing system.
Expected deliverables: design of new implants, development of new multi-material process machine.
Functionalization and in vitro testing: The goal in functionalization is to preserve biomaterial properties while modifying only its surface to possess desired recognition and specificity, providing new functionality such as osteoinduction and biocidal activity. Various approaches to functionalization of materials will be investigated including
- the use of particular ions in the mineral phase such as the use of fluoride or nitrogen ions in the synthesis of bioglasses to produce a biocidal activity;
- the use of antibacterial agents, such as bacteriophages or protein agents known as antimicrobial peptides which must be released in a controlled manner over time, to fight against resurgence of multiresistant bacteria to antibiotics;
- promote osteoinduction by the grafting of recombinant proteins fused to growth factors to promote osteogenesis or angiogenesis;
- surface modification (at nano scale) of the orthopaedic prosthesis by osteoinductor ceramic or metallic coating and
- the potential and benefit of using mesenchymal stem cells in in vitro cell culture: Improvement of biocompatibility and decrease of risk of infection by functionalization
Existing in vitro tests provide no information regarding the response of living, three dimensional bone to a biomaterial implant. Nor they do not take into account the effect of resorbability on mechanical properties. To generate a bone-implant interface for study, the most common approach is in vivo testing with small or large mammals. Less well known is the cultured calvarial model where the biomaterial is placed in contact with the surface of neonate rat bone to generate an ex vivo interface. The problem with all of these models is the use of animals, and there is a relative lack of standardisation compared to in vitro testing with cell lines. The applicants propose to develop a new three dimensional live bone model by culturing cells and generating extracellular matrix within a biomaterial scaffold in a laboratory setting. This bone model will for the first time enable generation of a bone-implant interface, and more complexity may be introduced, e.g. combined with a mucosal model in order to study the biocompatibility of novel permucosal implant materials: Validation by in vitro testing
Expected deliverables: proof of the bioactivity and of the improved biocompatibility of functionalized implant.
Information will be compiled throughout the COST Action to form the investigational medicinal product dossier and work will be carried out in line with the recommended ISO standards and good laboratory practise. In addition following the in vitro and in vivo work the applicants will apply to the Medicines and Healthcare products Regulatory Agency to seek approval for pre-clinical data: Medical assessment
The COST Action NEWGEN work programme can be summarised into focused work tasks that encompass the research, technological development and innovation activities and project management:
- Work task 0: Scientific and administrative coordination
- Work task 1: Design and end-user
- Work task 2: Medical assessment and environmental and industrial impacts
- Work task 3: Raw material synthesis and characterisations
- Work task 4: Process Machining development
- Work task 5: Whole process development
- Work task 6: Characterisation of parts
- Work task 7: Functionalization
- Work task 8: In vitro testing
- Work task 9: Dissemination
Scientific work plan methods and means
The common and best method to pursue the scientific work plan in the most efficient way is to base the Action on Working Groups (WG), promoting scientific exchange of ideas, and new information about research and opportunities through meetings, publications, training, short-term missions, etc. and generating concrete research project proposals for the development of new bone implants.
The COST Action will be divided in four WGs including actors of the different categories of partners:
Manufacturing and characterization of 3D-porous scaffolds
Functionalization of implants for improved functional and therapeutic effects
In vitro an in vivo evaluation of the performance