Development of Injectable Allograft Adipose Matrix for Soft Tissue Filling: From Conception to Clinical Trial

Background: There is a clinical need for an off-the-shelf bioinductive soft-tissue replacement in reconstructive surgery. Our group developed injectable Allograft Adipose Matrix (AAM) as a solution, derived from cadaveric human subcutaneous adipose tissue through a decellularization and milling process. The final form is lyophilized powder rehydrated before use. The aim was to demonstrate the translational development of AAM from conception to clinical study.

 

Methods: In vitro and animal studies (using immunocompromised and wild type rodent models) were conducted to determine cellular ingrowth, vasculogenesis, adipogenesis and volume retention.  A 16-week prospective clinical study evaluated subcutaneous AAM injection (2.5-5cc) of the dorsal wrist of 15 subjects to determine patient safety, graft retention, and histological characteristics. A clinical trial was then conducted by injecting 20cc of AAM into 6 individual abdominal subcutaneous sites of 10 subjects. Subjects were randomized to panniculectomy either 3 or 6 months after injection, and biopsies were taken at 1 and 2 months. Safety of AAM and histology of specimens obtained at biopsy and surgery were determined.

 

Results: In vitro seeding of ASCs on AAM, showed attachment and proliferation of ASCs for 3 days, followed by production of new matrix within 7 days and changes to adipocyte morphology. AAM injected on the dorsum of immunocompromised nude mice supported adipogenesis at 6 weeks, with progressive increase in adipocyte frequency at 12-24 weeks and graft retention  of 44±16% at 24 weeks. AAM injected in the dorsal flanks of immunocompetent Fisher rats showed higher graft retention (89±16%) up to 3 weeks, and induction of anti-inflammatory M2a macrophages as early as 72 hours compared to controls and alternative ECM derived products. The prospective clinical study evaluating dorsal wrist injections showed a graft retention of 47.14% at 16 weeks, with no histological evidence of inflammation or necrosis and no adverse events. The clinical trial demonstrated that larger volumes of AAM injections were tolerated well with no reactions. Clinical safety and graft retention were demonstrated at 6 months with histological evidence of adipogenesis and presence of endothelial cells. The only adverse event was surgical site infection in one out of 60 sites, which occurred after a biopsy.

 

Conclusions: AAM is a novel off-the-shelf adipose-derived injectable matrix, which represents a safe alternative for soft-tissue reconstruction.  Bio-inductive AAM shows favorable volume retention, cellular infiltration, and de-novo adipogenesis from endogenous precursor cells.