## 4 The Future--Where Are We Going? Twenty years have passed since the first implantation of a cell-seeded porous biomaterial was performed in a bone segmental defect of a human patient. In a paper published in 2001, [PERSON] et al. [364] reported the successful repair of large bone defects (4-8 cm) via custom-made porous hydroxyapatite scaffolds seeded with autologous BM-MSCs. Specifically, four patients were recruited in 1998 for this study after unsuccessful treatment by conventional orthopedic surgery. All patients recovered limb function within six to 12 months and, over a 6.5-year follow-up, none of them experienced major complications or reported significant complaints. No late fractures in the implant zones were observed [365]. This work was one of the milestones that paved the way for modern bone regenerative medicine. In addition, in 2001, a second fundamental report was published by [PERSON] et al. [366] who replaced an osseous defect in the distal phalanx of a patient's thumb, which was caused by an avulsion injury through the implantation of a coralline porous implant seeded with PDPCs that were previously expanded in vitro. At that time, this publication raised some debate in the scientific community given the availability of simpler options (from both technical and economic viewpoints), which could be selected to solve this specific clinical problem. Commenting on this article in the Editorial to the journal issue, [PERSON] and [PERSON] wrote that \"although some specialists in reconstructive hand surgery might consider this technique an unnecessarily complex and time-consuming approach to a simple clinical problem,\" this approach is \"an important effort to bring tissue engineering to the fields of hand surgery and reconstructive surgery\" [367]. Following these pioneering achievements, tremendous advancements have been carried out over the last two decades for the selection and isolations of suitable cell types for bone tissue engineering strategies, which has been reviewed in the present paper. A key goal of many studies has been to try overcoming the objections highlighted by [PERSON] and [PERSON] in 2001, i.e., the technical and economic burdens associated with cell-based tissue engineering strategies. In this regard, translation \"from bench to bed\" may be particularly difficult and draining. In fact, the combination of high innovation--which is not always positively accepted by the market and clinicians-, high complexity and high production/certification costs are the main critical issues to be overcome for a wide diffusion of cell-based tissue-engineered constructs. As critically discussed by [PERSON] in a valuable paper [368], the deepest \"valley of death\" where new technologies and products may be lost while moving from the bench to the bedside, is the technological transfer from lab-scale (academia and research centers) to industries and clinical implementation. The dream of all clinicians is to have an off-the-shelf cell-based product that is free from the typical drawbacks of tissue transplants (i.e., limited availability, need for additional surgery, and the risk of disease transmission) and is readily available to be used for bone regeneration in all patients [369], BTE has the potential to meet this complex challenge and become a feasible alternative to tissue transplantation, provided that a strategy for homogenously supplying oxygen and nutrients to the cells in the inner part of the implanted scaffold is developed [370]. Currently, various cells have been applied (alone or in combination with biomaterials) to accelerate bone repair in vivo with sophisticated outputs. However, the main critical question remains 'which cell source is the best for using in BTE strategies?' The answer to this query is not clear since there are pros and cons for each cell type. In general, several factors dictate the selection criteria of cells such as ease and cost of treatment as well as availability.