Question

1. As a biomedical engineer, your duty in a private medical device manufacturing company is to develop, manufacture, and CE certified osteoinductive bone tissue engineering scaffold. Select one proper scaffold and scaffold manufacturing method that would allow manufacturing osteoinductive scaffold, and briefly explain. Define and explain two different adequate vasculogenesis strategies that you can apply to your scaffold. This scaffold will be implantable and permeable (long term). Define and explain the biocompatibility process for CE certification. What would be the classification of your developed medical device? Please briefly explain CE certification process. What are the factors that affects classification of your medical device?

Answer 1

The role of Bone Tissue Engineering in the field of Regenerative Medicine has been the topic of substantial research over the past two decades. Technological advances have improved orthopaedic implants and surgical techniques for bone reconstruction. However, improvements in surgical techniques to reconstruct bone have been limited by the paucity of autologous materials available and donor site morbidity. Recent advances in the development of biomaterials have provided attractive alternatives to bone grafting expanding the surgical options for restoring the form and function of injured bone. Specifically, novel bioactive (second generation) biomaterials have been developed that are characterised by controlled action and reaction to the host tissue environment, whilst exhibiting controlled chemical breakdown and resorption with an ultimate replacement by regenerating tissue. Future generations of biomaterials (third generation) are designed to be not only osteoconductive but also osteoinductive, i.e. to stimulate regeneration of host tissues by combining tissue engineering and in situ tissue regeneration methods with a focus on novel applications. These techniques will lead to novel possibilities for tissue regeneration and repair. At present, tissue engineered constructs that may find future use as bone grafts for complex skeletal defects, whether from post-traumatic, degenerative, neoplastic or congenital/developmental "origin" require osseous reconstruction to ensure structural and functional integrity. Engineering functional bone using combinations of cells, scaffolds and bioactive factors is a promising strategy and a particular feature for future development in the area of hybrid materials which are able to exhibit suitable biomimetic and mechanical properties. This review will discuss the state of the art in this field and what we can expect from future generations of bone regeneration concepts.

Osteoinductive or “smart” biomaterials have the ability to induce ectopic bone formation by instructing its surrounding in vivo environment to form bone.28–30 Although the biological mechanisms of this phenomenon have not been fully elucidated, it is well recognized that these materials hold great potential for bone tissue regeneration. An array of biomaterial families have demonstrated having osteoinductive properties, including natural and synthetic ceramics (i.e., hydroxyapatite (HA) and variouscalcium phosphate compositions, and their composites (i.e., HA/ poly(lactic-co-glycolic acid) (PLGA). A number of studies have illustrated osteoinduc-tion by calcium phosphate (CaP)-based bioma-terials in various physical forms.31 Specifically, osteoinductivity has been demonstrated with CaP-based biomaterials in the form of sintered ceramics,32–36 cements,37,38 coatings,39,40 and coral-derived ceramics41–43 in a variety of animal models. Other ceramics, such as alumina ceramic and porous bioglass, have also been recently identi-fied as being osteoconductive.44 In addition, polymer/ceramic composites, such as PLGA/ HA, have been shown to be osteoinductive and to induce bone formation ectopically.45–50 However, it is critical to note that other material properties play a critical role in osteoinduction, aside from the chemical composition of the biomaterial, which may include porosity of the biomaterial implant and its surface properties, such as nano/micro topography. To some extent, the level of osteoinductivity also depends on the species used for the study (i.e., interspecies variation). Two main theories have been proposed to explain the observed osteoinductivity. The first is based on the biomaterial surface features that absorb and present osteoinductive factors to the surrounding cells. The second hypothesis is that the calcium phosphate–based materials release calcium and phosphate ions, which later influence stem cell differentiation into bone cells. No conclusive evidence exists for either of these hypotheses.

The term osteoconductive refers to the scaffold or matrix which stimulates bone cells to grow on its surface. Osteoinductive capacity of a bone graft is perhaps the most important property in bone healing as it refers to the stimulation of MSCs to differentiate into preosteoblasts to begin the bone-forming process.

The vascularization process is partly recapitulated in adults during physiological conditions that require nutrient and oxygen supply, such as tissue regeneration, wound healing, or in some cases disease progression such as tumor growth

Medical Device Directive is one of the most complex directive and one which involves strict vigilance by the European Authorities. Steps for CE marking for Medical Devices of Class 1s, IIa, IIb and III are as follows:

1. Implement a quality management system ISO 13485:2012 as per annex II & V of MDD (not required for class I non sterile non measuring devices).
2. Appoint an European authorized representative (required by non EU manufacturer only).
3. Apply General & product specific standards as applicable to the medical device particularly Bio-compatibility ( ISO 10993 series for Implants and IEC 60601 series for Electromedical products).
4. Prepare a technical file comprising of detailed manufacturing process, devices description, test reports, risk analysis, Instruction for Use, labeling, applicable standards etc.
5. Submit the technical file & QMS documents to notified body for approval.
6. Notified Body conducts onsite audit through approved auditors.

7 Translate IFUs & labels to the local language of the country to which you want to export.