**5. Clinical use**

#### **5.1. The regenerative cells**

The growing interest in this area of research has driven the adoption of adipose tissue and ADSCs in a wide number of clinical situations, medical fields and conditions for the repair and regeneration of acute and chronically damaged tissues, with an increasing number of trans‐ lational efforts. Clinical trials have been advanced in order to investigate the therapeutic potential and applicability of these cells based on the induction of their properties similar to that observed in BMSCs. An extensive great knowledge concerning the harvesting, character‐ ization and transplantation of ADSCs has been developed. Even so, current literature still lacks of strong evidence about the clinical potential of ADSCs and adipose tissue. In particular this may be due to the fact that human lipoaspirates may significantly differ in purity and molec‐ ular phenotype and that many reports have adopted heterogeneous populations of cells providing uncertain results. Remarkably, some problems still affect the correct interpretation of outcomes. One of the most significant issues limiting the interpretation of clinical progres‐ sion is the lack of standardization in defining ADSCs, since both SVF and ADSCs may be used. [4] Another issue is whether ADSCs operate on tissue regeneration through direct transdifferentiation or paracrine mechanisms based on the secretion of numerous cytokines and growth factors. Thus, standardization of a method and improvement of current preclinical data may allow direct comparison of different results as well as a better definition of clinical potential of ADSCs. Current preclinical and clinical data of such cell-based therapies should include the osteogenic, chondrogenic, adipogenic, muscular, epithelial and neurogenic differentiation of progenitor, endothelial, and mesenchymal stem cells involved. Thus, skin, bone, cartilage, muscle, liver, kidney, cardiac, neural tissue, pancreas represent some of the most prominent clinical targets on which these therapies are focused. ADSCs are commonly adopted in clinical settings in surgical fields such as: cell-enriched lipotransfers, soft tissue augmentations and reconstructions of defects after trauma or oncologic surgery, healing of chronic wounds (phase 1 trials for the healing of recurrent Crohn's fistulae), skin regeneration and rejuvenation (repair of damages induced by aging or radiations), scar remodeling. In addition, they have been adopted in the treatment of cardiovascular disease, metabolic disease and encephalopathy (cerebral infarction) and a wide range of other surgical needs by ortho‐ pedic surgeons, oral and maxillofacial surgeons and cardiac surgeons. Indeed, the clinical application of adipose tissue relies on convincing results but the full therapeutic potential of ADSCs may still need further investigation.

#### *5.1.1. The "Lipofilling technique"*

Fat graft has been initially adopted to generate adipose tissue in the treatment of contour deformity or volumetric defects. The "lipofilling technique" has been used for many years and it has become rapidly popular especially in aesthetic surgery to improve cosmetic results in facial surgery. In fact it may be considered an ideal filler since it is totally biocompatible, readily available, inexpensive and it enables good aesthetic results. More variable are the application of fat injection in reconstructive surgical treatments. For example in breast reconstruction the indication of lipofilling include micromastia, tuberous breasts, Poland syndrome, postlumpectomy deformity, post-mastectomy deformity, sequelae of post-radiotherapy (every anatomical region previously subjected to radiotherapy is subject to fat injection), refinement of secondary reconstructions after flap or prosthesis reconstruction and nipple reconstruction. In head and neck reconstructive surgeries it has been used to correct Treacher Collins syn‐ drome o other cranio-synostosis. In burns, lipofilling has been adopted to improve the structural features of extracellular matrix in the treatment of burn sequaele, such as pathologic scars, with the aim to restore a more physiologic skin architecture. The lipofilling is also a valuable option to enhance volumes in facial hypotrophies, for example in patients affected by HIV-related lipo-distrophy. In addition, fat injection has proved to be very useful to improve local vascularization and trophism in chronic ulcers, especially vascular or posttraumatic ulcers.

**Figure 2.** Injection of autologous adipose tissue ("lipofilling technique") in a scar.

#### *5.1.2. Clinical trials with ADSCs*

**5. Clinical use**

**5.1. The regenerative cells**

192 Regenerative Medicine and Tissue Engineering

ADSCs may still need further investigation.

*5.1.1. The "Lipofilling technique"*

The growing interest in this area of research has driven the adoption of adipose tissue and ADSCs in a wide number of clinical situations, medical fields and conditions for the repair and regeneration of acute and chronically damaged tissues, with an increasing number of trans‐ lational efforts. Clinical trials have been advanced in order to investigate the therapeutic potential and applicability of these cells based on the induction of their properties similar to that observed in BMSCs. An extensive great knowledge concerning the harvesting, character‐ ization and transplantation of ADSCs has been developed. Even so, current literature still lacks of strong evidence about the clinical potential of ADSCs and adipose tissue. In particular this may be due to the fact that human lipoaspirates may significantly differ in purity and molec‐ ular phenotype and that many reports have adopted heterogeneous populations of cells providing uncertain results. Remarkably, some problems still affect the correct interpretation of outcomes. One of the most significant issues limiting the interpretation of clinical progres‐ sion is the lack of standardization in defining ADSCs, since both SVF and ADSCs may be used. [4] Another issue is whether ADSCs operate on tissue regeneration through direct transdifferentiation or paracrine mechanisms based on the secretion of numerous cytokines and growth factors. Thus, standardization of a method and improvement of current preclinical data may allow direct comparison of different results as well as a better definition of clinical potential of ADSCs. Current preclinical and clinical data of such cell-based therapies should include the osteogenic, chondrogenic, adipogenic, muscular, epithelial and neurogenic differentiation of progenitor, endothelial, and mesenchymal stem cells involved. Thus, skin, bone, cartilage, muscle, liver, kidney, cardiac, neural tissue, pancreas represent some of the most prominent clinical targets on which these therapies are focused. ADSCs are commonly adopted in clinical settings in surgical fields such as: cell-enriched lipotransfers, soft tissue augmentations and reconstructions of defects after trauma or oncologic surgery, healing of chronic wounds (phase 1 trials for the healing of recurrent Crohn's fistulae), skin regeneration and rejuvenation (repair of damages induced by aging or radiations), scar remodeling. In addition, they have been adopted in the treatment of cardiovascular disease, metabolic disease and encephalopathy (cerebral infarction) and a wide range of other surgical needs by ortho‐ pedic surgeons, oral and maxillofacial surgeons and cardiac surgeons. Indeed, the clinical application of adipose tissue relies on convincing results but the full therapeutic potential of

Fat graft has been initially adopted to generate adipose tissue in the treatment of contour deformity or volumetric defects. The "lipofilling technique" has been used for many years and it has become rapidly popular especially in aesthetic surgery to improve cosmetic results in facial surgery. In fact it may be considered an ideal filler since it is totally biocompatible, readily available, inexpensive and it enables good aesthetic results. More variable are the application of fat injection in reconstructive surgical treatments. For example in breast reconstruction the

Most of clinical trials on humans are based on previous experiments on animal models. The evidence of the ability of ADSCs to differentiate into cells of non-mesodermal origin has been tested in some models in treatment of several diseases. The ADSC-derived hepatocytes transplanted into nude mice restored liver function and freshly isolated ADSCs could differ‐ entiated into hepatocytes after intrasplenic transplantation into nude mice in vivo, supporting their application in clinical setting. [21] However clinical trials are still mostly lacking of promising results. [4] A recent study showed that the direct injection of ADSCs could restore blood flow in a mouse ischemic hindlimb model, as confirmed by clinical data. [22] The myogenic differentiation of ADSCs may be used in the treatment of muscular diseases such as Duchenne dystrophy and for regenerative cell therapy in heart failure. [23] Other novel potential clinical uses of ADSCs include the treatment of Alzheimer disease, of multiple sclerosis due to the anti-inflammatory effect of ADSCs, of neurogenic bladder and other neurologic disorders. A preliminary study showed that peri-urethral injection of autologous ADSCs acts positively in stress urinary after prostatectomy. Regarding current clinical applications of ADSCs, apart from a phase III trial on the treatment of Crohn's fistula, most clinical trials are in phase I. Beside the use in breast reconstruction, trials are in progress to treat acute myocardial infarction and chronic myocardial ischemia by intracoronary injection of SVF. Other trials are focused on the treatment of cirrhosis and of diabetes I or II. [4] Another trial adopted ADSCs (after purification and expansion) for the management of fistulas associated or not to Crohn's disease: results demonstrated an efficient control of inflammation and an improvement of healing process, most likely due to paracrine action that cells differ‐ entiation. Another trial investigated the restoration of volumes in hypotrophic scars after subcutaneous injection of ADSCs. Only two trials have studied the effect of ADSCs on chronic critical limb ischemia: the first adopting intra-muscular injection, the second by intravenous injection in diabetic patients. The literature regarding different clinical trials [Table 4.]demon‐ strates that ADSCs-based therapies are a concrete opportunity but despite these results, molecular, cellular e biological features of these cells are still uncertain and it is also unclear if regenerative therapy is related to their differentiation potential or paracrine activity: indeed, more appropriate in vivo investigations are necessary.


**Table 4.** Clinical trials using adipose-derived stem cells (ADSCs) or stromal vascular fraction (SVF).
