Interpenetrating Networks for Delivery Systems Team Members Claire Flanagan Ashley Huth Max Michalski Adam Rieves Advisor Professor Kristyn Masters PhD Department of Biomedical Engineering Client Professor John Kao PhD UW School of Pharmacy Department of Biomedical Engineering Abstract Interpenetrating networks that are composed of gelatin cross linked with PEG diacrylate provide a promising solution to decrease healing time for large surface area wounds However the current reconstitution and administration methods of this product are clinically undesirable The current method requires 60 C water The goal of this project was to create a novel method to reconstitute the components of an interpenetrating network in order to achieve long term storage and successful IPN application at room temperature After extensive testing a final solution of 20mL acetate citrate buffer 2g of 90 110 bloom gelatin and 20mg I 2959 photoinitiator was determined to provide the best dissolution Alterations were also made in the design of the spray bottle to improve administration techniques Introduction Background Large surface area and chronic non healing wounds significantly impair the quality of life for millions of people in the United States Harding et al 2002 These wounds are characterized by a loss of skin and underlying tissue which do not heal properly with conventional types of treatment Falanga V 2004 Instead intensive treatment is required that is costly and requires a lengthy recovery period Hence solutions have been investigated to aid and advance the wound healing process Numerous bioactive dressings as well as skin substitutes have been created however few are currently operational in a clinical setting Harding et al 2002 Our client Professor John W Kao has created a biocompatible interpenetrating network IPN that offers a drug delivery mechanism and promotes healing in large surface area wounds This particular interpenetrating network is a mixture of crosslinked polyethylene glycoldiacrylate PEG dA and dissolved gelatin PEG dA as shown in Figure 1 is a polymer which can be synthesized in a variety of molecular weights of which the three most common are 600 Dalton 2kD 3 4kD 600D PEG dA is a liquid while the others are a powder When PEG dA is added to a photoinitiator and exposed to a UV light the diacrylate groups crosslink via free radical polymerization Nakayama 1999 When PEG dA is mixed with gelatin and crosslinked the gelatin becomes entrapped in the PEG dA 2 Figure 1 Structure of top poly ethylene glycol and bottom poly ethylene glycol diacrylate The components from which an IPN is made were carefully chosen by its creator for their desired biological properties First PEG dA is bioinert meaning that it does not elicit a response from a biological tissue into which it is inserted Nakayama 1999 Additionally gelatin is derived from collagen a naturally occurring substance in mammals Rhee 1999 For this reason it is biocompatible in solution When an IPN forms the photo polymerized PEG dA provides a matrix that holds the gelatin The resulting network provides a perfectly conforming wound dressing Interpenetrating networks are beneficial for healing advancement of large surface area wounds due their physical and chemical properties First IPNs are able to cover large surface area wounds that are often irregularly shaped The fluid nature of IPNs allows them to properly conform to these irregularly shaped wounds promoting rapid and uniform healing However IPNs are effective barriers against foreign microbial infections In addition IPNs can be created to contain therapeutics in either a solvent form or as a covalent attachment to gelatin Kao et al 2003 The drugs are then administered to the patient via diffusion or cleavage respectively further aiding in the healing process Professor Kao s laboratory has obtained positive results in a wound treatment study utilizing IPNs Kao et al 2003 However while IPNs offer an exceptional solution to improved healing time and drug delivery there are many problems associated with the current administration techniques 3 Current Methods Current IPN preparation and administration methods Figure 2 are only suitable for a laboratory setting Preparation in a clinical setting has been limited by the necessity for gelatin to be mixed with a heated solvent at 60 degrees Celsius for five minutes to ensure complete dissolution However in a clinical setting a heating element would not be available so modifications are necessary Also administration methods are inadequate because syringes are currently being used yet IPNs are intended to treat large surface area wounds Syringes provide for tedious and uneven administration of the IPN solution In order to begin using IPNs in a clinical setting these issues must be resolved 1 2 3 Heat Mix Ingredients drug s in single container Inject Syringe is use to administer solution 4 Cure in 30 sec to obtain a rubbery film 7 6 5 Cover Clean Sustained Release while the IPN biodegrades Day Day 1 3 Day 7 Kao W J Figure 2 Current method for administering an interpenetrating network to a wound Main ingredients used include PEGda gelatin and a photoinitiator Problem Statement 4 Interpenetrating networks are a type of biomaterials that polymerize in situ and have been used in drug delivery wound healing and tissue engineering applications The goal of our project has been to develop a novel delivery mechanism and create a simple reconstitution method for the components of an interpenetrating network This design must be suitable for a clinical setting and the final product must also satisfy the design constraints outlined by Dr Kao Design Constraints Dr Kao has instituted several restrictions to our design approaches The most important restriction to consider is the clinical applicability of the final result In order for a product to be clinically accepted it must fit seamlessly into the hospital environment The utility of our product centers on several factors including shelf life the ability to reconstitute each component without the need for additional equipment and ease of application Regarding shelf life Dr Kao has requested that our equipment be one time use only Disposable medical equipment is more practical because sterilization is not required after application Similarly single use products reduce risk of contamination due to minimized exposure to oxidizing agents and microbial invasion Overall the capacity for prolonged storage in a
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