EFFECT OF LONG-TERM APPLICATION OF EPINEPHRINE ON RAT SKIN VASCULATURE: EXPERIMENTAL STUDY ERCAN KARACAOG Æ LU, M.D., 1 * HAKAN C Ë ERMIK, M.D., 2 TU È RKAN YURDUN, 3 AND RICHARD J. ZIENOWICZ, M.D. 4 As a potent vasoconstrictor, epinephrine is used ubiquitously in plastic surgery. It is typically delivered subcutaneously in very low concentrations over a brief time interval. We are aware of no reports describing the long-term release of epi- nephrine as an independent agent to the soft tissues for the purpose of causing prolonged local vasoconstriction. This study was designed to address two goals: first, to investigate the effect of long-term local release of epinephrine from a drug delivery system on rat abdominal skin vasculature; secondly, to evaluate the pharmacological properties of this drug delivery system (DDS). Thirty male Sprague-Dawley rats, weighing 300À400 g, were included in the study. Ani- mals were subdivided into two groups of 15 each. Group A (control group) and Group B (experimental group) were treated with saline and epinephrine-loaded microspheres (msps), respectively. The manufacturing process and for- mulation studies of the DDS are described. In vivo assays revealed a 7-day sustained release of epinephrine. After 7 days, neither residual nor supraphysiologic release of epi- nephrine was shown with high-performance liquid chroma- tography (HPLC). Histological studies with hematoxylin- eosin and periodic acid Schiff revealed a statistically signifi- cant increase in number of vessels as well as their diameter and wall thickness (P <0.05). Epinephrine release via this msp/DDS predictably induces local vasoconstriction over a time sequence known to be optimally associated with hy- poxia and promotion of vascular augmentation. This model can be valuable in sustaining hemostasis during long-lasting (more than a few hours) surgical procedures by its long- acting vasoconstructive effect. The system's ability to in- tentionally cause vascular augmentation also bodes great potential in flap and graft surgery. ã 2002 Wiley-Liss, Inc. MICROSURGERY 22:288±294 2002 Epinephrine, with its a-1 adrenergic properties on skin and subcutaneous tissue, is an extremely potent vaso- constrictor. Concentrations as low as 1:400,000 provide sufficient vasoconstriction to decrease hemorrhaging at the operative field. For this reason it has enjoyed long- standing use in most plastic surgery procedures. It is frequently added to other local anesthetics to prolong their clinical duration of action by slowing resorption as a consequence of diminished local blood flow. Univer- sally, epinephrine is used in very low concentrations (1:100.000À1:400.000) for limited time periods. In this study,weenlistedepinephrineforanovelreasonthathas not been previously described. We designed an experi- mental model to deliver epinephrine to a discrete area of local soft tissues for a limited time. and dose parameters were adjustable. We will refer to this system as a biode- gradablemicrosphere(msp)drugdeliverysystem(DDS). Msp/DDS, using various kinds of biodegradable polymers, have been studied extensively in the past two decades. 1À7 Recently, investigators in the ®elds of me- dicinal chemistry, pharmaceutics, and tissue engineering tested completely biodegradable and injectable msp/ DDS for the long-term controlled release of a variety of pharmacological agents. 3À10 Microspheres are fine spherical particles with diam- eters less than 10 lm that can serve as a vehicle for drug transport and delivery (Fig. 1). Biodegradable polymers investigated for DDS are either natural (e.g., albumin, collagen, hyaluronic acid, chitosan, or erythrocytes) or synthetic (polyglycolic acid and other aliphatic polyes- ters) materials. 9 During the manufacturing process, the drug to be deliveredisaddedasanaqueoussolutiontothepolymer solution. This biphasic mixture is mechanically homog- enized, such that small aqueous droplets are suspended inthepolymersolution.Thepolymerisprecipitatedinto asolidphase,trappingtheaqueousdroplets.Thewateris then sublimated away, leaving the drug behind in nu- 1 Division of Plastic Surgery, Golcuk Naval Hospital, Kocaeli, Turkey 2 Department of Pathology, Haydarpasa Training Hospital, GATA Military Medical School, Istanbul, Turkey 3 Department of Pharmaceutical Biotechnology, School of Pharmacy, Uni- versity of Marmara, Istanbul, Turkey 4 Division of Plastic Surgery, Brown University School of Medicine, Provi- dence, Rhode Island *Correspondence to: Ercan Karacaog Ælu, M.D., Hizirbey cad Kume Sok Bal- kaya, Apt. B, Blok No. 19, Daire 3, Goztepe, Istanbul 81060, Turkey. E-mail: drercanka@yahoo.com Received 18 April 2002; Accepted 30 July 2002 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/micr.10055 ã 2002 Wiley-Liss, Inc.