New Horizon in In Vivo Microdialysis of Large Molecules OPEN FLOW MICROPERFUSION (OFM) Products and Contract Research Services Cerebral OFM

Sampling CSF from Cisterna Magna

Dermal/Adipose OFM Microdialysis vs OFM New Horizon in In Vivo Microdialysis of Large Molecules OPEN FLOW MICROPERFUSION (OFM) Products and Contract Research Services q OFM is a connuous ssue sampling technique based on minimally invasive membrane-free probes q OFM enables direct contact with the intersal fluid compartment q Valuable tool in Neuroscience , Dermal, Oncology, Biomarker and PK- PD research q Cerebral OFM (cOFM), dermal OFM (dOFM) and adipose ssue OFM (aOFM)

OFM Derives Beer Data and Drives Beer Decisions: ü Direct contact with the extracellular compartment ü Uncompromised Intact blood-brain barrier ü Probe free membrane ü No limitaon in molecular size ü No limitaon on lipophilicity or protein binding ü Compeve edge in characterizing neurotransmiers, pepde and proteins, anbodies, transporters, enzymes, bound and unbound drugs, and even vesicles and cells from the extracellular space Cerebral OFM (cOFM) Products and Contract Research Services § cOFM allow us to see beyond the blood-brain barrier, and to invesgate the concentraons and acon of a neurological agent directly at the target site – in brain ssue. § cOFM allows connuous monitoring of PK in intact brain ssue. Our experiments show that 15 days aer probe implantaon, the BBB has healed and has re- established its funcon. Thus, cOFM facilitates the connuous measurement of substance transport over the intact BBB. § BBB funcon can be connuously monitored in any animal to demonstrate intactness of the BBB. § cOFM probes implanted in Cisterna Magna can be used to sample undiluted and unfiltered CSF connuously at a rate of 25 μl/h and physiologically replenished. § cOFM provides daily me-resolved measurements in each subject for several hours at a me, reducing the number of subjects required. § Costs and development me can be reduced because cOFM provides the pharmacological profile of a drug at an earlier phase in drug development. Companies learn at a very early stage whether a neurological agent is a potenal therapeuc agent, reducing cost and development me. Cerebral OFM (cOFM) Products and Contract Research Services

Product Highlights q CE-cerfied innovave OFM Pump, probes and accessories for preclinical use q Portable pump (0.1 – 10 µl/min) allowing delta push-pull operaon q Enclosed and completely sealed perfusion bags q FEP tubing material: 0.8 mm diameter, 5mm length q Patent for pumps and probes pending New Horizon in In Vivo Microdialysis of Large Molecules Cerebral OFM (cOFM) Products

Infusion Bag OFM PUMP cOFM Guide Cannula cOFM Probes

Tubing Sets Raturn™ based Automated Sampling System Cerebral OFM (cOFM) Products and Contract Research Services References: 1. Pieber et al., Open Flow Microperfusion: An Alternave Method to Microdialysis? In: M. Müller (ed.), Microdialysis in Drug Development, AAPS Advances in the Pharmaceucal Sciences Series, (2013) , 283-302. 2. Birngruber et al., Cerebral open flow microperfusion: A new in vivo technique for connuous measurement of substance transport across the intact blood–brain barrier, Clinical and Experimental Pharmacology and Physiology (2013) 40, 864–871. 3. Birngruber et al., Enhanced Doxorubicin Delivery to the Brain Administered Through Glutathione PEGylated Liposomal Doxorubicin (2B3-101) as Compared with Generic Caelyx, R /Doxil R —A Cerebral Open Flow Microperfusion Pilot Study, Journal of Pharmaceucal Sciences (2014) 103(7), 1945-8. 4. Birngruber et al., Long-Term Implanted cOFM Probe Causes Minimal Tissue Reacon in the Brain, PLOS ONE (2014), 9(3), 1-9. 5. Ghosh et al., Assessment of Blood-Brain Barrier Funcon and the Neuroinflammatory Response in the Rat Brain by Using Cerebral Open Flow Microperfusion (cOFM), PLOS ONE (2014), 9(5), 1-7. 6. Birngruber and Sinner, Cerebral open flow microperfusion (cOFM) an innovave interface to brain ssue, Drug Discovery Today: Technologies, (2016), 20, 19-25.

Ask BASi for further informaon about cOFM ✓We can build OFM capabilities in your lab ✓We can facilitate OFM contract research services Dermal OFM (dOFM) and Adipose OFM (aOFM) Products and Contract Research Services

§ OFM allow us to focus at the target tissue level § Transport and effects of drugs in adipose tissue e.g., insulins § Transport and effects of drugs in the dermis after topical or systemic application; e.g., topical glucocorticoids and systemic antibodies with psoriatic or inflammatory animal models § Glucose-clamp techniques, in combination with aOFM, allow investigation of insulin sensitivity as well as concentration of insulin and its effect in the subcutaneous tissue. § PK/PD studies - such studies are invaluable for pharmaceuticals with a site of action in the subcutaneous adipose tissue as well for basic research e.g., in fat metabolism and insulin resistance § aOFM can provide valuable information very early in preclinical phases of drug testing. It can reveal whether the drug reaches its target after oral, subcutaneous, topical, intravenous or other modes of administration and allows compartmental PK modeling. § dOFM provides PK/PD information for dermatological substances directly from the site of action, thus providing valuable information very early in preclinical development. Dermal OFM (dOFM) and Adipose OFM (aOFM) Products and Contract Research Services Product Highlights

q CE-cerfied innovave OFM Pump, probes and accessories q Minimally invasive membrane free probe with a 0.36 X 15 mm sampling mesh and a 0.5 mm inseron needle q FEP tubing material: 0.8 mm diameter, 5mm length q Wearable / Portable pump (0.1 – 10 µl/min) allowing delta push-pull operaon q Enclosed and completely sealed perfusion bags q Patents for pumps and probes pending

Reference: 1. Pieber et al., Open Flow Microperfusion: An Alternave Method to Microdialysis? In: M. Müller (ed.), Microdialysis in Drug Development, AAPS Advances in the Pharmaceucal Sciences Series, (2013) , 283-302.

Ask BASi for further informaon about dOFM and aOFM ✓We can build OFM capabilities in your lab ✓We can facilitate OFM contract research services Dermal OFM (dOFM) and Adipose OFM (aOFM) Products

Probe

Tubing Sets

Infusion Bag for OFM Pump OFM PUMP