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Investigators in tissue engineering are required to concentrate not only on their current research but also on its relationship with expected outcomes in science and treatment improvement. Ethical questions appearing along tissue engineering research process considering bench-to-bedside translational pathway are complex and each research step along the translational progression requires researchers in tissue engineering to make moral decisions, from bench level and preclinical research to early stage human trials.
This research is centered in ethical challenges and issues at every step of investigation of a particular translational technology of tissue engineering, namely tissue engineered skeletal muscle (TESM) construct.
Issues at in vitro lab level cover data integrity, appropriateness of results reporting and dissemination, provision of results yielded to suit for further progress of the research. Issues at in vivo lab level cover relevant animal models. Issues of clinical level cover main challenges appearing in first-in-human tests comprising selection of patients, identification of ambiguity and the determination of success.
Skeletal muscle tissue is the biggest tissue in human bodies.
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It is responsible for 60% of the total body weight and it is crucial for generating forces for movement. Up to certain loss, the muscle is able to regenerate tissue upon injury. Beyond that, it cannot fully regenerate itself and its function. This loss can significantly impact the life-quality of patients by losing the operating skill of the system. The most frequent reasons for SM injuries are traffic accidents, surgical and orthopedic situation, blast traumas or sport injuries that lead to loss of muscle (Dennis and Kosnik, 2000; Liuetal.
, 2012). The structure of SM is entirely related to its function. The tissue is an ordered structure comprising parallel fibers.
The regeneration process of muscle is quite complex process. Different cells interact with the environment and each other, to produce the outcomes starting from regenerative process to pathological cases like inflammation (Koopmanetal., 2014).
Research in tissue engineering makes use of methods which combine of cells, tissues with diverse supporting technologies such as capsules and scaffolds and bioreactors, in order to improve tissues or other biomaterials that can replace or enhance biochemical and physiological functions damaged by injury or disease (Griffith, L. G., & Swartz, M. A., 2006). Scientific areas like material science, cell biology, molecular biology, chemistry, medicine and engineering are involved in this field. In 1993 Vacanti and Langer first introduced the term of tissue engineering to the wider scientific community. The definition they have given is still in use today and claims that the ultimate target of tissue engineering is creation and enhancement of biological substitutes supporting, improving, or restoring tissue function (Vacanti, J. P., & Langer, R., 1999).
Thus, TE can bypass the tissue damage associated problems that is currently being treated with grafts, mechanical devices, or surgically. These three therapeutic treatments have improved and saved the lives of countless patients; however they have several disadvantages. Examples of demonstration of important limitations of an organ graft can be graft rejection and the absence of a donor, to provide all demand across the world. In the case of mechanical devices it is their inability to perform all the tissue associated functions and to prevent a progressive impairment of the patient. And finally, surgical treatment can cause to long-term problems (Lalan, S., Pomerantseva, I., & Vacanti, J. P., 2001). Thus, the necessity of provision of more accurate solutions for tissue recovery in clinics arises tissue engineering.
Much TE research are stuck in pre-clinical stages. When ethical issues are frequently faced in the stage when human trials are started, there are still many issues at the bench of research. (8) These are data integrity, interpretation of results, data integrity and ensuring that each study is constructed and conducted that way, that it can be used in the next research. (9) It is important to define at each stage that the outcomes of the research may bring us not forward, but in another direction entirely, to expand and advance the knowledge and to determine new possibilities of further research.
Using of animal models at the stages before clinical, is essential in respect with the success of regenerative engineering. There are some alternatives for animal models such as computer modelling and or arrays of body on a chip organoid, but they still have a lot of issues and restricts that stop the progress. The correct choice of animals and their use can assist to ensure that the translation from animal model to human-subject will be covered by the principle of Jonathan Kimmelman “modest translational distance”. Briefly speaking, it is the number of leaps on the way to human from animal, so it can be described as a measure of uncertainty (Kimmelman, 2009). At the beginning of clinical research, human-subjects are asked about the risk of failure if there is not currently adequate data on clinical intervention.
There is a lot of information about ethical issues in bioengineering and human involving trials. For TE, as well as for regenerative engineering, the most crucial problem occurs at the early clinical stage. These are translation into human patients, selection of potential human-subjects, designing of trials etc.
Before starting research with first in human trials, there is a list of questions that should be adequately answered:
For ethical considerations there are two key aspects of clinical research. These are scientific validity and value. A valid research is the study where the approach, technology, design and etc. tend to provide desirable answers to all unknown moments, even if the answers are negative. Moreover, valuable research is the kind of research where social and scientific meaning is clear. Regarding translational value, it can be divided to three: reciprocal, iterative and collateral. Reciprocal value underlines the necessity of the preclinical work. Iterative value assists to provide information on the clinical trial itself by highlighting what can be effectively used for clinical trial as the trial moves further.
Collateral value is useful for some different trials, by creating new knowledge, techniques, data and experience that are expanded to researcher of similar field or studies. When choosing the human-subjects it is vital to find patients who can provide accurate scientific data and are able to inform about participation in studies still at the beginning of research. It is necessary for researchers to inform accurately not only the potential patients, but also the public and media. This way the risk of misconception might be reduced. Sometimes, after research, the following examining of patient-subjects is ignored, it is frequently not only about the budget and success or failure of the study, but also in the relation with patients.
In this case study, the tissue engineered skeletal muscle comprises of a cell-seeded biomaterial construction which was used to enable repairing or regeneration of cells in a muscle loss pathology or after damage. This kind of tissue engineering technology aims to switch the standard method of care used nowadays, which is the use of host or cadaveric muscle flaps for remodeling. Using host muscle flaps is a way of creating a new, less negatively affecting region of muscle loss in order to repair the original injury.
Using cadaveric muscle flaps requires an immunosuppressive regimen. Distinctively, using tissue engineered skeletal muscle, ideally, would also require surgical implantation, but would not cause any additional damages or require an immunosuppression (Baker etal., 2015). In further human subject studies, the TESM construction would start a week before the implantation of cell from a biopsy of a human subject. Those cells are likely to be enlarged in culture and finally seeded onto the scaffold, which is biocompatible. Then, in accordance to the type of TESM technology applied, the scaffold, seeded with cells, can be directed to further guidance for development (Machingaletal., 2011). At the end of the process, the design will be sutured into the emptiness of the tissue.
Firstly, the concept for a skeletal muscle must be conducted in vitro and only after this, it can be provided to animal testing. Thus, it can last for years. Consequently, such work would be continued by in vivo testing, which tends to build a model of animal muscle injury that would be useful for investigator for treatment purpose. In vivo studies are frequently inherently long-lasting, because each study must be conducted for long enough period, to catch the full potential of regeneration for the pathology that muscle has. The time also depends on the injury itself, as for minor ones it varies from days, for example, sport injuries. But for larger muscle damage it can vary to months (Corona, 2010). The difficulty that this research may face includes ethical issues at each step, concluding up to clinical application. Therefore, this case study observes those ethical aspects at all early, pre-clinical and in clinical work stages.
As it was abovementioned, for preclinical trials the main focus of ethical consideration must be on data integrity. It includes the value of the science and seeks advance of future research. Every study should result in a professional guidance for researchers in the following studies. In addition, for animal studies, scientists need to apply the rule of three Rs (“Replace”, “Reduce”, “Refine”) to the maximum level.
Ethical considerations at the first trials at the bench consists of the following:
It is important to consider the potential advantage of the technology during providing translation on TESM, even at the earliest stage of research. This work at the bench is likely to lead to helping treat some defects from the birth or cancer etc. Thus, it is obviously, that the ethical consideration at this stage is extremely essential. For example, if something determined in the protocol but not mentioned in the documentary, it may affect successful translation of research work to clinic and may result in loosing achieved progress. All details such as cell culture, usage of instruments and preparing reagents are all vital as well as its documentation at any stage (Joffee, 2008). Researchers should be aware of any potential failure from the beginning. TESM research is a complex work, so it is needed to be unbiased. For this purpose, the third research group should be involved, to check and repeat the experiments. Acting this way is making the work easier if applied in the early stage. It also proves the concept for animal and clinical trials.
In TESM research, culture of cells for muscle on scaffolds can assist in the use and developing technologies, as an example of reciprocal value, the use of muscle cell in other purpose for application (Yazdani, 2009).
One of the most challenging tasks during research is facing the three Rs. Relating to the first R, which is “Replace” – there is no alternative to the use of animals in TESM technology. Studying the cell culture on the scaffolds itself can help to study the process, but without necessary environment it does not go further. The next two Rs are “Reduce” and “Refine” help to make sure if that the number of presented animals is minimal, and the damage to them is also the least affecting. Also, they are cared and looked after according to installed rules (National Research Council, 2011).
Reduction means that the best suitable animals are determined and the number is sufficient for achieving the best results. For instance, it is unconscious to use small group of animals for the big amount of TESM interventions. Due to the following problems it may cause and inefficiency of tests.
Refinement expresses not just appropriate analgesia for animals, but also making sure that each individual animal is used only for the right purpose and the use is targeted. The study comprises of developing the technique on small animals and further application on a large animal type (e.g. sheep, pigs).
As TESM technology is a multiplex process, which includes cellular, material and bioreactor compounds, they all must be entirely functional and operating. In opposite case, the risk of damage is increased. Species to species exchange must also be under control as much as it can be done, especially moving from animal model to humans. As the amount of loss or volume of muscle injury cannot be counted and standardized, to create an injury in animal muscles via surgery is a difficult process in both ethical and regulatory meanings. Therefore, it is conscious to make up a uniform and less damaging trauma in animal models to justify the concept. Consequently, this process is quite challenging, at there will always be difference between animals and human-subjects.
Furthermore, while matching animals to humans in terms of muscle injuries, the following aspects must be considered:
For the best result, in animal research, there is a need in a maximum control of injury. If the injury created and it is allowed to heal itself without surgical inclusion, it implies the negative control of technology. It is necessary to study to what extent the intervention is needed in regeneration. Positive control entails the use of treatment or flap transfer. It is required as in order to define the effectiveness of TESM and compare it with current standard way of caring.
The final objective of the research is to find out if the TESM can replace transferring of autologous and allogeneic flap. Ultimately, translational distance affects data transparency and validity of work. There are internal and external validity. Internal validity is a strength of influences coming from trial results. To Improve it, validity must have random variability. So, for tissue engineered skeletal muscle, the is one option – making sure that the work is repeated by previous lab work and maintaining comprehensive report notes.
External validity – is more challenging due to the big difference between animals and human models. This may be solved by the third-party group of researchers to repeat some of the research in order to ensure the efficacy in animal studies, thus the scientists can share their experience with each other. Moreover, the obtained data must be published for further studies. Failures of translation incline the prediction that this technology with low bugs of ultimate success will lead it to clinical trials.
Production of results that can help researchers develop the next study is the responsibility of each clinical test. Since the improvement of clinical practice is the final aim of medical research, validity, as well as value should be considered while designing all tests. The design and guidance of testing must also ensure research subjects to be protected: identification and minimization of harm risks to subjects is necessary, and their possibility or lack should be considered for direct benefit; this covers defining failure and success, as well as exploring what should be done with patients when/if the intervention of experiment is unsuccessful. Taking these considerations into account in TESM studies at the first stage and at an early stage can create special questions.
The fair and correct selection of subject is a key element necessary for the scientific and ethic basement of design of clinical tests. Should the first participants in the TESM design study be patients with wide range of injuries or minor defects? Which are most corresponding control groups? TESM study in the early stages in humans will certainly concentrate only on the recovery of defects and injuries of comparably small volumes, mostly due to the necessity of vascular supply development or provision. Vascularization is a crucial aspect of investigation in tissue engineering, which needs further enhancement (Lovett, Lee, Edwards, & Kaplan, 2009). However, it is also possible to consider the inclusion of patient-subjects with more complicated injuries, if concept data can be collected before standard amputation or repair. Thus, a TESM study at an early stage can also be carried out on patients with more complicated lesions, if there is enough time for this before attempting standard treatment using a flap or cadaveric muscle. Designing and conduction of such research, so that the following conditions are met, would be crucial:
Moreover, collection of data from patients who decide not to carry out any repairs may be useful. In the TESM testing at early stages, when there is no barrier represented by the vascular supply, randomizing patient subjects who would choose standard treatment rather than fictitious surgery or no treatment is not ethically justified if the design needs refusal of a fairly effective standard treatment (Emanuel, Wendler, & Grady, 2000; Horng, S., & Miller, 2003; Macklin, 1999).
A patient who voluntarily participates in a clinical testing should first of all know that she or he is an investigation partner who, having joined the research, will continue research to promote the field despite the outcome. Candidate patients must be informed that the purpose of the research is to discover whether TESM construct can refine appearance of muscle damage area and recover its function. Results for patients are obscure and will change. Study is an investigation of a possible solution, not a cure. In TESM studies, the need to obtain consent for the participation of patients with recent traumatic damages may hamper the effective transmission of important information. Even if candidate patients are well-informed, they can still firmly believe that, despite the failure risk, TESM will definitely work in their case. In a such situation, this may lead to expression of reasonable optimism or significant underestimation of harm risks, overestimation of possible advantages, and mistaken acceptance of investigation as a treatment by patients — it could be due to influence by therapeutic misconception (King, Henderson, Churchill, & Davis, 2005; Weinfurt, Seils, Lin, Sulmasy, Astrow, Hurwitz, ... & Meropol, 2012). Minimization of therapeutic misconception can often be reached by mindful discussion and management of expectations with candidate patients during interviews and screening before registration, as well as by continuing discussion while participating in testing. Emphasis of consent for patients with recent damages will be important in the TESM study (Illes, J., Reimer, J. C., & Kwon, B. K., 2011).
In the first-in-human trial interventions relating to TESM there are some essential “unknowns”. Created injuries in animals will not be identical to injuries occurring in patients owing to the presence of anatomical differences, and tendency of injuries to have different complexities and geometries. Generally, each injury has its unique complexity. Therefore, investigators in the first-in-human TESM testing must determine (and afterwards introduce to candidate patients) what is unknown and unpredictable. It does not depend on the design of a research, as it applies to both pilot and possibility studies and multi-arm trials.
When translating research in tissue engineering, such as TESM, to human patients, the including risks are not only the harm risks related to all procedures along surgical manipulation, such as implant site infection, but the risk of not meeting patient expectations, as well. TESM expose patient's body to permanent change, which needs additional surgery operation to be reversible (Taylor, Caplan, & Macchiarini, 2014). Candidate patients must be informed that in the case of a failure of the experimental intervention, correction of the defect would require an additional surgery operation, which may entail the experimental implant replacing with a conventional flap, which attracts all the additional surgery risks and possibly adds one more risk of flap deviation. In addition, a TESM construct may not be physically rejected, but may nevertheless not meet the patient's expectations regarding functional recovery or appearance. To reduce dissatisfaction with the result of TESM recovery, patient expectations should be taken into account and discussed prior to registration — an act analogous to the standard practice of consent in reconstructive and plastic surgery.
To evaluate the success of the TESM study, several approaches might be applied. For assessing the repairs of muscle, electromyography or any physical and mechanical tests can be conducted by a therapist. One more significant metric is the appearance of treated muscle, as the aesthetic aspect of muscle can largely affect the quality of life and confidence of a patient, even if the muscle is not entirely functional. In addition, the patients-subjects can carry an information on personal metrics of quality before and after surgery. This assessment might be too individual and personal depending on each patient’s preference. Before clinical trials, these metrics must be determined and evaluated by patients, including process before, during and after repair. To define the impact of skeletal muscle intervention, for some human-subjects, the general well-being, life-quality and mental health must be precisely assessed before the surgery.
Those abovementioned quality assessments cannot fully interpret on the preference of patients and consequently varies between each individual. Success, by achieving the pre-defined objectives, focuses on regeneration of damaged muscle or on the extend of muscle operating skills, from weight-lifting to professional athletics. Regarding this, research results of clinical trials in TESM might have much more subjective assessment than in other typical trials. Research group should negotiate the possible outcomes with patients-subjects, to learn what they expect from the research work. Such discussion should be conducted instantly after the surgery as well as a long-term following-up quality of life. The outcomes of operating functionality and physiology measures can be identified, however, in the end, if patients are not satisfied with the result this can be deemed as failure. Identically, if patients are satisfied with a non-operating repair, due to the remarkable appearance will be deemed as a success. Therefore, as success is extremely vital in translations, the research group must define what is success and what it means in TESM investigation to each individual.
Undoubtedly, well-constructed translation research has a great value even if the outcome unsuccessful. Each failure study helps investigate potential collateral and reciprocal value. When patients with some condition react distinctively from other patients, the reciprocal value can be found for animals with the same condition.
The technique used might be advanced from one patient to the next and many other trial improvements might also be provided. Ultimately, revealing more specialists to TESM is a significant predictable collateral value. For example, the TESM scaffold itself can have new unexpected application in surgery therapy. Hence, research that provides iterative, reciprocal and collateral value can be effective despite the obvious failure, as it gives hope that the research may keep going to further clinical trials.
Ethical Considerations in Tissue Engineering: From Bench to Bedside. (2024, Feb 22). Retrieved from https://studymoose.com/document/ethical-considerations-in-tissue-engineering-from-bench-to-bedside
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