Adipose tissue in bone regeneration - stem cell source and beyond

Table 1 Factors that influence adipose-derived mesenchymal stem cells secretome content and release[99-101]

Donor	Tissue	Culture conditions	Cell manipulation
Species	Type (sWAT, vWAT)	2D vs 3D (spheroid culture, cell sheets), suspension culture	Preconditioning (IFN-γ, TNF-α, LPS)
Age	Anatomic location (abdominal, brachial, mammary)	Hypoxia	Differentiation (osteogenic, adipogenic)
BMD (obesity)	Method of procurement (lipectomy, liposuction)	Plating density, co-culture	Physical factors (electromagnetic fields, pulsed electromagnetic fields)
Disease (T2D, metabolic syndrome, lipodystrophy)	Methods of tissue processing, enzymatic digestion, mechanical trituration	Media formulation (serum containing versus serum free, growth factor addition)

T2D: Type 2 diabetes mellitus; sWAT: Subcutaneous white adipose tissue; vWAT: Visceral white adipose tissue; IFN-γ: Interferon gamma; TNF-α: Tumor necrosis factor alpha; LPS: Lipopolysaccharides; BMD: Bone mineral density.

Table 2 Clinical trials using adipose-derived mesenchymal stem cells for bone regeneration registered on clinicaltrials.gov (June 2021)

Trial registration	Ref.	Study design	Group/cohort	Intervention	Location	Status
NCT01218945	Calcagni[168]	Observational/prospective	Overweight, non-metabolic disease, 17-80 yr	To pre-engineer large synthetic bone grafts and study the vascularization process in vivo	University of Zurich, Switzerland	Completed December 2012
NCT01532076	Saxer and Jakob[169]	Allocation: Randomized. Intervention model: Parallel assignment. Masking: Single (outcomes assessor). Primary purpose: Treatment	Patients with osteoporotic fractures, age 18-70 yr	Cellularized composite graft augmentation liposuction, cell isolation, embedding of SVF cells in fibrin gel, wrapping around hydroxyapatite granules compared to acellular grafts	University Hospital, Basel, Switzerland	Terminated/slow recruitment rate/last update 17 September 2014
NCT01643655	Yoon[170]	Allocation: N/A. Intervention model: Single group assignment. Masking: None (open label). Primary purpose: Treatment	Avascular necrosis femoral head Steinberg I-III/pre-collapse, age 17-70 yr	Autologous adipose tissue-derived MSCs transplantation into the femoral head/infusion of autologous adipose-derived mesenchymal stem cells. Dose: 1 × 108 cells/3 mL	R-Bio SMG-SNU Boramae Medical Center	Recruitment completed/last update 31 August 2017
NCT02140528	Gourabi et al[171]	Allocation: Randomized. Intervention model: Parallel assignment. Masking: Double (participant, investigator). Primary purpose: Treatment	Closed shaft tibial fracture, age 18-65 yr	Injection of adipose-derived mesenchymal stem cell in the site of tibia fracture. Other name: Stem cell transplantation compared to Placebo	Royan Institute Tehran, Iran	Completed/last update 27 April 2017
NCT03269409	Sierra[172]	Interventional, allocation: Randomized. Intervention model: Parallel assignment. Masking: Quadruple (participant, care provider, investigator, outcomes assessor). Primary purpose: Treatment	Patients with ONFH pre-collapse, non-posttraumatic, 22-70 yr of age	Adipose-derived regenerative cells harvested through autologous liposuction processed using the Celution 800/GP System (Cytori Therapeutics) transplanted into the femoral head after standard of care hip decompression compared to standard decompression and Ringer solution	Mayo Clinic, United States	Suspended (updating study protocol, consent form and study SOP protocol) March 2021
NCT02307435	Dilogo[173]	Allocation: N/A. Intervention model: Single group assignment. Masking: None (open label). Primary purpose: Treatment	Fracture nonunion metaphyseal fibrous defect, age 19-30 yr	Experimental: Implantation group implantation group will receive ADSC/UCMASC/BMSCs and HA-CaSO4. Intervention: Biological: MSC	University of Indonesia, Jakarta	Unknown/last update 4 December 2014
NCT03678831	Pasquier[174]	Observational, case-control prospective	Arthritic post-menopausal patients with knee prosthetic replacement	Adipocyte isolation from distal femoral epiphysis and subcutaneous adipose tissue at the surgery site; classical piece removal during prosthetic replacement of the knee	University Hospital, Lille, France	Recruiting/April 2021
NCT04377880	Fodzo[175]	Observational study	Osteoporotic patients undergoing total joint arthroplasty	Osteoblastic response to medullary adipocytes of commercial origin analysed by gene expression and correlation with clinical data regarding osteoporosis and microtomography	University Hospital, Lille	May 2021

ADSC: Adipose-derived mesenchymal stem cells; UCMASC: Umbilical cord mesenchymal stem cell; BMSC: Bone marrow stem cell; MSC: Marrow stem cell; ONFH: Osteonecrosis of the femoral head; SOP: Standard operating procedures; SVF: Stromal vascular fraction.