Introduction: In complex nerve injuries, critical functions are often left unreconstructed because not enough autologous nerve graft can be harvested. Accordingly, the need for a clinically useful substitute for autologous nerve grafts for the reconstruction of peripheral nerve defects is indisputable. We have previously reported the use of acellular peripheral nerve allografts as an alternative to autologous nerve grafting. We hypothesize that mechanical collapse of endoneurial conduits prevents effective axonal regeneration through acellular biomatrices derived ex vivo from peripheral nerves. If patency of the endoneurial conduits can be maintained during axonal regeneration, perhaps through the use of hydrogels (extracellular matrix molecules suspended in an aqueous medium) then end-organ function may be improved following nerve grafting. We therefore have designed experiments to test this hypothesis in a 4 cm nerve gap rat model. Methods: Four cm peripheral nerve segments were harvested from F344 rat hindlimbs. These peripheral nerve segments were made acellular using a series of detergent solutions. The acellular nerves were then treated with one four hydrogels (Matrigel, Type I collagen, 0.5% alginate and 1.0% alginate). Each hydrogel was applied to the nerves singly or in two layers. The nerves were sectioned and stained with toluidine blue. Identically-treated nerves are about to be implanted into recipient F344 rats. There will be nine experimental groups. We will use a 4x2 design in which four types of hydrogel are applied in either one or two layers. Additionally a control group consisting of plain acellular nerve without hydrogel will be used. The treated grafts will be implanted into 4 cm peroneal nerve gaps in F344 rats. After four months, in vitro isometric force measurements will be performed. The EDL muscle and nerve graft will undergo biochemical, histomorphometric, immunohistochemical, and ultrastructural analysis and the results from the hydrogel and untreated groups will be compared. Results: Toluidine blue sections of the acellular nerves demonstrated that endoneurial conduits were present after addition of hydrogel and prior to implantation. Results from the remainder of the study are pending. Conclusion: Modifications to the extracellular matrix of acellular peripheral nerve may be a promising avenue of investigation. Depending on the outcome of the implantation experiments the hypothesis that prevention of mechanical collapse using hydrogels may be supported.