Suitability Assessment of Inert Polymers as Tracheal Replacement Material / Tissue Engineered Implant ScaffoldIntro to Tracheal replacement: objectives and scope. Include differences (clinical and regulatory) between a medical device, a tissue engineered medical device and a tissue transplant, and the relevance of “compassionate use” exemptions.1.    IntroductionThis report is based on a BBC documentary titled “Fatal Experiments: The Downfall of a Supersurgeon”, in which synthetic polymer tracheae which were seeded with stem cells were implanted into various patients by Italian thoracic surgeon Dr. Paolo Macchiarini. In this documentary, it was clear that prior to the inert polymer scaffolds implantation, these implants did not undergo animal testing. During these surgeries, the synthetic tracheae were used as part of full and partial replacements to the patients’ own trachea. However, a number of debates arose about Dr. Macchiarini ‘s methods. Debates on topics such as ethics, and whether some of his patients were ill enough to undergo a tracheal replacement. Matters such as this, caused various investigations into Dr. Macchiarini and his methods.In this case, the implants were made from a polymer known as POSS-PCU (Polyhedral Oligomeric Silsesquioxane Poly(carbonate-urea) Urethane). They were then reseeded with human bone marrow stem cells in order to replicate normal tracheal tissue mechanical properties and function. In the area of tissue engineering, this is what is known, as artificial grafting, where man made tissue scaffolds that are analogous to the original tissue which are used in the body. These methods were endorsed by high level institutes such as the Karolinska Institute in Sweden, where Dr. Macchiarini carried out the main research for his methods, but despite initial reports describing the procedure as a success, as time passed the tracheae implants started to fail. This was due to several reasons including bacterial infection and migration of the implant, which resulted in a number of fatalities.The aim of this report is to make a critical assessment on the likelihood of the success of inert polymers as tracheal replacement material / tissue engineered implant scaffold and their clinical outcomes, which could be known prior to the clinical use of these materials. 2.    BackgroundA tracheal transplant is only advisable if a resection is an incapable procedure to deal with the patient’s issue. In the case of synthetic tracheal implants which were focused on in this documentary, patient conditions ranged from tracheal cancer, to patients born with deformed tracheas. The trachea is one of the few organs that are exceptionally difficult to transplant because of the technical difficulty to restore the blood supply to the implant. The trachea is made up of cartilage rings which collapse slightly to allow peristalsis to take play in the oesophagus, and blood is supplied to this area with very small numerous and small blood vessels, hence the difficulties. (Piere Delaere, 2016).Although this documentary focuses on synthetic polymer tracheas, other methods of tissue engineering and tissue transplants are currently being researched in the area of tracheal implants, specifically in the area of xenografts and allografts. In recent times major research has been implemented specifically on decellularization using ionic reagents such as Sodium Dodecyl sulfate followed by stem cell reseeding with a goal of hoping to create off the shelf organs. Dr. Macchiarini used methods similar to this prior to use of synthetic polymer tracheas where an allograft was created using decellularized trachea taken from a deceased human and reseeded it with the patient’s bone marrow stem cells. The use of synthetic polymers and tissue engineered donor scaffolds will be compared throughout this report.  3.    ObjectivesThe aim of this report is to make a critical assessment on the likelihood of the success of inert polymers as tracheal replacement material / tissue engineered implant scaffold and their clinical outcomes, which could be known prior to the clinical use of these materials. This will be achieved by discussing the topic under the following headings:Biocompatibility and tissue attachment issues that could be anticipated at junction of inert polymer and tissue interface in an open airway applicationThe likelihood of immediate post-operative immune function / infection control over an 8 cm length of open airway “seeded” synthetic tracheal implant in comparison with functional mucosal epithelium of healthy native tissueAssessment of probability of cellular invasion/differentiation/ proliferation of appropriate cell types and sell assembly of functional vascularized tissue on inert, but stem cell seeded plastic airway tubes. (smooth muscle, epithelial, angiogenic etc.) 4.      Anticipated Biocompatibility IssuesBiocompatibility can be defined as “the ability of a material to perform with an appropriate host response in a specific application” (DeBarra, 2018). The material POSS-PCU which was used as the tracheal replacement was intended to be bioinert. However, all implants with some having a more miniscule effect than others, will always illicit a biological response. It can be anticipated that one of four implant responses were possible, these are listed in table 1 below:Implant Response1Encapsulation2Integration3Extrusion4ResorptionTable 1: Possible Implant Response Results (DeBarra, 2018)Since every implant will illicit a biological response, each of these four implant responses would undergo the same host response sequence according to Anderson 2011.  Host Response Sequence1Injury2Blood-material interactions3Provisional matrix formation4Acute inflammation5Granulation tissue6Chronic inflammation7Foreign body reaction8Fibrosis/fibrous capsule developmentTable 2: Sequence of host reactions post medical device implantation (Anderson, 2001)It is important to note that host’s response to the illicit biological reaction will depend on a number of factors including the type of blood-material interaction. The synthetic POSS-PCU trachea had been intended to be integrated into the hosts system, meaning it hoped to show similar properties to the normal host tissue without causing complications, however, consideration about replication of the host trachea tissue defence mechanisms should have been made prior to implantation of the synthetic trachea, as these tend to do a bad job of replicating this (Dickinson & Bisno, 1989).4.1.           General Factors Affecting BiocompatibilityThe reactions and processes that can occur between a material and an organism are complex and depend on many factors including but not limited to:Factors Affecting Biocompatibility1The tissue the material is in contact with2The organism3Time of assessment4Factors connected with the individual e.g Age, sex, genetic make-up, general healthTable 3: Factors Affecting Biocompatibility (DeBarra, 2018)The appropriate biocompatibility assessment prior to clinical use with regards to the parameters in table 3 for the synthetic trachea would more than likely have given a poor outlook on the implant. Dr Macchiarini and his team were under pressure by investors to provide results, so no clinical trials were completed with only a minimal amount of animal tests completed. In regard to the first implant, Mr. Beyene who had received the implant due to a tumour growth in his trachea, his implant was initially deemed success. However, the patient passed away two years later. The autopsy report showed chronic inflammation between the implant and the surrounding tissue, which caused the implant to collapse, causing suffocation. There was also issues regarding the attachment of the implant. Had the parameter of “time assessment” in table 3 been correctly tested and assessed prior to clinical use, the could have been avoided.Regarding the tissue in question, there had been research in the area for methods of trachea replacement prior to Dr. Macchiarini’s first implant. No method of trachea transplant including the tissue engineering of a synthetic trachea had been successful long term in a safe and practicable manner  (Grillo, 2002). Similarly, the declining health of Mr. Beyene and previous health issues had been blamed for the failure of the implant, but the general health of the patient is one of the main factors affecting biocompatibility, and this should have been accounted for.4.2.           Inert Polymer and Tissue Interface JunctionAs previously mentioned, the trachea is one of the most complex tissues in the body due to the nature of blood supply and the arrangement of cartilage rings along the tissue, so it’s understandable that according to (Delaere & Van Raemdonck , 2014) “Cells have never been observed to adhere, grow & regenerate into complex tissues when applied to synthetic scaffolds”. However, since all implants with the exception of one, were partial and not full synthetic trachea implants, it was important that the interaction with the implant and the remaining host trachea tissue had no complications.POSS-PCU is not a toxic material itself, however after it was implanted, the junction with the remaining tracheal tissue became chronically infected due to fungal infection, causing the implant to collapse, damaging the implant/tissue interface junction and blocking an airway. This could have been anticipated however. As the trachea is an organ which constantly comes in contact with bacteria provided through respiration. Unsterile pre-clinical testing should have been conducted to replicate conditions that leave the anastomosis site open to bacterial contamination.The anastomosis site between the implant and the trachea can be temporarily protected by wrapping the covering the site with vascularized tissue, such as omentum. This does not fully protect the anastomosis site however, but delays complications (Piere Delaere, 2016)Figure 1: Anastomosis between synthetic trachea and host trachea tissue (Piere Delaere, 2016)Ideally the anastomosis site would have healed, and collagen synthesis occurred in the weeks post the procedure, but basement membrane collagens are synthesised by epithelia and epithelial cells in blood vessels. Collagen synthesis is regulated by interactions between growth hormones and cytokines (DeBarra, 2018). Due to fungal infection, this process is unable to happen, as was seen in one of Dr Macchiarini’s patients where the autopsy reported that the synthetic trachea could easily be “pulled out”, conveying that collagen synthesis did not occur at the anastomosis site due to fungal infection. It should also be noted that just as the implant will have an effect on the surrounding tissue, the surrounding tissue will also affect the implant both chemically and physically.BibliographyAnderson, J., 2001. Biological response to materials. Annual Review, pp. 81 – 110.DeBarra, E., 2018. Biomaterials 1 , s.l.: s.n.Delaere, P. & Van Raemdonck , D., 2014. The Trachea: The First Tissue-Engineered Organ?. The Journal of Thoracic and Cardiovascular Surgery , 147(4), pp. 1128-1132.Dickinson, G. & Bisno, A., 1989. Infections Associated with Indwelling Devices:. Antimicrobial Agents and Chemitherapy, 33(5), pp. 602 – 207.Grillo, H., 2002. Tracheal Replacement: A Critical Review. The Annals of Thoracic Surgery , 73(6), pp. 1995-2004.Piere Delaere, D. V. R., 2016. Tracheal Replacement , s.l.: NCBI .