Synthesis and Characterization of Novel Polyurethane Drug Delivery Systems

Selective delivery of drugs to localized regions of tissue within the body is a complex problem, representing one path through which the efficacy of many pharmaceutical compounds can be enhanced. Many pharmaceutical compounds show excellent activity in vitro, but their uses are severely limited in vivo. Unstable active conformations, limited membrane diffusion, rapid metabolism and/or clearance, decreased solubility, and dose-limiting systemic toxicity are just a few areas in which potential problems exist, halting drug development. Compounds exist possessing ideal pharmacologic activity for treating specific disease states, but they are simply unable to be delivered in adequate quantities or in the proper active conformation to the target site in the body. The following dissertation details the synthesis, characterization, and performance of a series of polyurethane drug delivery systems based on amino acids and the simple carbohydrates. The materials were synthesized from lysine diisocyanate (LDI) and glycerol with the aid of various tertiary amine and organometallic urethane catalysts. Candidate drugs were incorporated into the materials by way of labile urethane and urea linkages; subsequent drug release relied on the passive hydrolysis of the tethering bonds. Drug release from the materials correlated to material morphology, urethane catalyst, and chemical functionality of the incorporated drug. A single-phase polyurethane material was designed, synthesized, and shown capable of simultaneously releasing multiple pharmacologic agents at different rates. Finally, naturally occurring ionic ligands were incorporated into the LDI-glycerol polyurethanes to alter their swelling characteristics and release kinetics. This endeavor has resulted in the formulation of a series of polyurethane materials, capable of long-term controlled release of pharmacologic agents within the body. The structure-function relationships elucidated provide key design criteria, which can ultimately be used to develop such advanced degradable polyurethane materials

Pediatric Upper Extremity Replantation: Courage in the Face of a Life-altering Injury

Background:. Pediatric plastic surgeons perform reconstructive surgeries for various congenital, oncologic, and traumatic injuries. Methods:. Our Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC) Plastic Surgery team was tasked to care for a young man who suffered a proximal humeral amputation of his dominant upper extremity. Results:. A multidisciplinary team collaborated throughout his entire acute care and postoperative course, guiding treatment and care in effort to maximize function of his replanted extremity. Conclusions:. This case report details the patient’s unique journey and highlights his determination and courage to return back to a normal life

Delivery of adipose-derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration

INTRODUCTION Peripheral nerve damage is associated with high long-term morbidity. Because of beneficial secretome, immunomodulatory effects, and ease of clinical translation, transplantation with adipose-derived stem cells (ASC) represents a promising therapeutic modality. METHODS Effect of ASC delivery in poloxamer hydrogel was assessed in a rat sciatic nerve model of critical-sized (1.5 cm) peripheral nerve injury. Nerve/muscle unit regeneration was assessed via immunostaining explanted nerve, quantitative polymerase chain reaction (qPCR), and histological analysis of reinnervating gastrocnemius muscle. RESULTS On the basis of viability data, 10% poloxamer hydrogel was selected for in vivo study. Six weeks after transection and repair, the group treated with poloxamer delivered ASCs demonstrated longest axonal regrowth. The qPCR results indicated that the inclusion of ASCs appeared to result in expression of factors that aid in reinnervating muscle tissue. DISCUSSION Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve 58: 251-260, 2018

Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates.

Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps \u3e2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line-derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for \u3e50 days in a 5-centimeter nerve defect in a rhesus macaque model. The GDNF-eluting conduit (PCL/GDNF) was compared to a median nerve autograft and a PCL conduit containing empty microspheres (PCL/Empty). Functional testing demonstrated similar functional recovery between the PCL/GDNF-treated group (75.64 ± 10.28%) and the autograft-treated group (77.49 ± 19.28%); both groups were statistically improved compared to PCL/Empty-treated group (44.95 ± 26.94%). Nerve conduction velocity 1 year after surgery was increased in the PCL/GDNF-treated macaques (31.41 ± 15.34 meters/second) compared to autograft (25.45 ± 3.96 meters/second) and PCL/Empty (12.60 ± 3.89 meters/second) treatment. Histological analyses included assessment of Schwann cell presence, myelination of axons, nerve fiber density, an

Long-gap peripheral nerve repair through sustained release of a neurotrophic factor in nonhuman primates

Severe injuries to peripheral nerves are challenging to repair. Standard-of-care treatment for nerve gaps >2 to 3 centimeters is autografting; however, autografting can result in neuroma formation, loss of sensory function at the donor site, and increased operative time. To address the need for a synthetic nerve conduit to treat large nerve gaps, we investigated a biodegradable poly(caprolactone) (PCL) conduit with embedded double-walled polymeric microspheres encapsulating glial cell line-derived neurotrophic factor (GDNF) capable of providing a sustained release of GDNF for >50 days in a 5-centimeter nerve defect in a rhesus macaque model. The GDNF-eluting conduit (PCL/GDNF) was compared to a median nerve autograft and a PCL conduit containing empty microspheres (PCL/Empty). Functional testing demonstrated similar functional recovery between the PCL/GDNF-treated group (75.64 ± 10.28%) and the autograft-treated group (77.49 ± 19.28%); both groups were statistically improved compared to PCL/Empty-treated group (44.95 ± 26.94%). Nerve conduction velocity 1 year after surgery was increased in the PCL/GDNF-treated macaques (31.41 ± 15.34 meters/second) compared to autograft (25.45 ± 3.96 meters/second) and PCL/Empty (12.60 ± 3.89 meters/second) treatment. Histological analyses included assessment of Schwann cell presence, myelination of axons, nerve fiber density, and g-ratio. PCL/GDNF group exhibited a statistically greater average area occupied by individual Schwann cells at the distal nerve (11.60 ± 33.01 μm2) compared to autograft (4.62 ± 3.99 μm2) and PCL/Empty (4.52 ± 5.16 μm2) treatment groups. This study demonstrates the efficacious bridging of a long peripheral nerve gap in a nonhuman primate model using an acellular, biodegradable nerve conduit