Development of a combined radiation and full thickness burn injury minipig model to study the effects of uncultured adipose-derived regenerative cell therapy in wound healing.
To develop an approach that models the cutaneous healing that occurs in a patient with full thickness thermal burn injury complicated by total body radiation exposure sufficient to induce sub-lethal prodromal symptoms. An assessment of the effects of an autologous cell therapy on wound healing on thermal burn injury with concomitant radiation exposure was used to validate the utility of the model.



Göttingen minipigs were subjected to a 1.2 Gy total body irradiation by exposure to a 6 MV X-ray linear accelerator followed by ∼10 cm2full thickness burns (pre-heated brass block with calibrated spring). Three days after injury, wounds were excised to the underlying fascia and each animal was randomized to receive treatment with autologous adipose-derived regenerative cells (ADRC) delivered by local or intravenous injection, or vehicle control. Blood counts were used to assess radiation-induced marrow suppression. All animals were followed using digital imaging to assess wound healing. Full-thickness biopsies were obtained at 7, 14, 21 and 30 days' post-treatment.



Compared to animals receiving burn injury alone, significant transient neutropenia and thrombocytopenia were observed in irradiated subjects with average neutrophil nadir of 0.79 × 103/μl (day 15) and platelet nadir of 60 × 103/μl (day 12). Wound closure through a combination of contraction and epithelialization from the wound edges occurred over a period of approximately 28 days' post excision and treatment. Re-epithelialization was accelerated in wounds treated with ADRC (mean 3.5-fold increase at 2 weeks post-treatment relative to control). This acceleration was accompanied by an average 67% increase in blood vessel density and 30% increase in matrix (collagen) deposition. Similar results were observed when ADRC were injected either directly into the wound or by intravenous administration.



Although preliminary, this study provides a reproducible minipig model of thermal burn injury complicated by myelosuppressive total body irradiation that utilizes standardized procedures to evaluate novel countermeasures for potential use following attack by an improvised nuclear device.
a Cytori Therapeutics Inc , San Diego , CA , USA.
Philippe
P
Foubert
b Lovelace Respiratory Research Institute , Albuquerque , NM , USA.
Melanie
M
Doyle-Eisele
a Cytori Therapeutics Inc , San Diego , CA , USA.
Andreina
A
Gonzalez
b Lovelace Respiratory Research Institute , Albuquerque , NM , USA.
Felipe
F
Berard
b Lovelace Respiratory Research Institute , Albuquerque , NM , USA.
Waylon
W
Weber
a Cytori Therapeutics Inc , San Diego , CA , USA.
Diana
D
Zafra
a Cytori Therapeutics Inc , San Diego , CA , USA.
Zeni
Z
Alfonso
a Cytori Therapeutics Inc , San Diego , CA , USA.
Sherry
S
Zhao
c UCSD Medical Center, University of California , San Diego , CA , USA.
Mayer
M
Tenenhaus
a Cytori Therapeutics Inc , San Diego , CA , USA.
John K
JK
Fraser
D017667:Adipocytes / Q000166:cytology; D000818:Animals; D002056:Burns / Q000473:pathology* / Q000628:therapy*; D008297:Male; D011832:Radiation Injuries / Q000473:pathology* / Q000628:therapy*; D012867:Skin / Q000293:injuries / Q000473:pathology / Q000528:radiation effects; D033581:Stem Cell Transplantation / Q000379:methods*; D013552:Swine; D013556:Swine, Miniature; D016896:Treatment Outcome; D014945:Wound Healing / Q000502:physiology*
Adipose-derived regenerative cells; combined injuries; radiation; thermal burn