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Surgical reconstruction of tendon injuries is challenging. Classic reconstructive techniques and tendon transplantation have some significant limitations and tissue engineering is a newer option. Despite significant development in tissue engineering technologies, the role of tissue engineering in tendon healing is still unclear. There are many tissueengineered products that are commercially available in the market, but most of them have not passed animal and clinical studies, and the behaviour of host immune response to these types of products has not been investigated. Researchers have also focused on in vitro investigations and because of the differences between ex vivo and in vivo situations, translation of their results to clinical practice is of great concern and generally hard to follow. To increase the impact of tissue engineering in tendon healing, more information concerning the structure of tendons, their injuries, healing and host immune response together with the characteristics of biomaterials is needed to produce a more effective tissue-engineered product with the aim to substitute the classic reconstructive methods with the new tissue engineering approaches. This review was aimed to introduce the most important issues in the relationship between tissue engineering and tendon regenerative medicine with the hope that this information would be valuable for those who have concerns about tendon healing. Introduction Treatment of tendon injuries is challenging1,2. Classic surgical reconstructive methods have significant limitations with unclear outcomes, especially in tendon injuries havinglarge tendon deficits3,4. Tendon transplantation is the only available option when the injured tendons cannot be repaired with classic surgical techniques2,3. Natural grafts can be divided into three major groups including autografts, allografts and xenografts2,5,6. All of them have their own significant limitations. For autografts, these limitations include availability of the autograft of the same size, shape and physiological characteristics of the normal tissue at the recipient site, donor site morbidity and cosmetic concerns, need for another surgical procedure and the time-consuming nature of the second procedure5. For allografts, these limitations are the availability of a healthy graft, risk of infection and transmission of fatal viral diseases (e.g. HIV or hepatitis), inefficiency of the graft to incorporate with the healing of the recipient site, rejection of the graft, re-injury due to the low biomechanical performance of the allografts and ethical concerns2,6,7. Limitations of the xenografts are similar to that of allografts, but their rejection rate is higher and their value in regenerative medicine because of insufficient experimental and clinical trials studies is questionable. Also, the presence of many unknown zoonotic diseases in animals, about which we have no information, could be another major concern6,8,9. For the above reasons, tissue engineering has been introduced to reduce these limitations and improve the outcome of incorporation of the tissueengineered grafts and improve the healing processes of injured tendons5,10,11. In the last decade, tissue engineering has been improved and much advancement has been achieved12,13. Several types of scaffolds with different technologies have been introduced so that nowadays there are many commercially available tissue-engineered products in the market13. However, most of these tissue-engineered products have not passed in vivo tests and most of the tissue-engineered researches have mainly focused on in vitro assays6,12,14. In addition, in vivo studies regarding the role of tissue-engineered products on regenerative medicine have not focused on mechanistic researches, and they have only observed the qualitative results with poor subjective data5,6. Therefore, there are many controversies between the results of the in vivo studies and there are also many differences between the sources, designing and preparation methods of the tissue-engineered grafts, which make their comparison hard to follow5,7,15,16. Regardless of the efficacy of these tissue-engineered products, there are some great concerns that should be addressed in future studies13. This study was aimed to introduce the role of tissue engineering in tendon reconstructive surgery and regenerative medicine, and has focused on * Corresponding author Email: dr.ali.moshiri@gmail.com 1 Division of Surgery, Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran 2 Department of Pathology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

Role of tissue engineering in tendon reconstructive surgery and regenerative medicine: Current concepts, approaches and concerns