Laboratory for Biomaterials and Drug Delivery

Boston, MA, United States

Laboratory for Biomaterials and Drug Delivery

Boston, MA, United States
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Timko B.P.,Laboratory for Biomaterials and Drug Delivery | Timko B.P.,Massachusetts Institute of Technology | Arruebo M.,Networking Research Center in Bioengineering | Arruebo M.,University of Zaragoza | And 14 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

A reservoir that could be remotely triggered to release a drug would enable the patient or physician to achieve on-demand, reproducible, repeated, and tunable dosing. Such a device would allow precise adjustment of dosage to desired effect, with a consequent minimization of toxicity, and could obviate repeated drug administrations or device implantations, enhancing patient compliance. It should exhibit low off-state leakage to minimize basal effects, and tunable on-state release profiles that could be adjusted from pulsatile to sustained in real time. Despite the clear clinical need for a device that meets these criteria, none has been reported to date to our knowledge. To address this deficiency, we developed an implantable reservoir capped by a nanocomposite membrane whose permeability was modulated by irradiation with a near-infrared laser. Irradiated devices could exhibit sustained onstate drug release for at least 3 h, and could reproducibly deliver short pulses over at least 10 cycles, with an on/off ratio of 30. Devices containing aspart, a fast-acting insulin analog, could achieve glycemic control after s.c. Implantation in diabetic rats, with reproducible dosing controlled by the intensity and timing of irradiation over a 2-wk period. These devices can be loaded with a wide range of drug types, and therefore represent a platform technology that might be used to address a wide variety of clinical indications.

Monteiro I.P.,Laboratory for Biomaterials and Drug Delivery | Monteiro I.P.,Massachusetts Institute of Technology | Monteiro I.P.,European Institute of Excellence on Tissue Engineering and Regenerative Medicine | Monteiro I.P.,University of Minho | And 16 more authors.
Acta Biomaterialia | Year: 2014

We have developed a bilayered dermal-epidermal scaffold for application in the treatment of full-thickness skin defects. The dermal component gels in situ and adapts to the lesion shape, delivering human dermal fibroblasts in a matrix of fibrin and cross-linked hyaluronic acid modified with a cell adhesionpromoting peptide. Fibroblasts were able to form a tridimensional matrix due to material features such as tailored mechanical properties, presence of protease-degradable elements and cell-binding ligands. The epidermal component is a robust membrane containing cross-linked hyaluronic acid and poly- L-lysine, on which keratinocytes were able to attach and to form a monolayer. Amine-aldehyde bonding at the interface between the two components allows the formation of a tightly bound composite scaffold. Both parts of the scaffold were designed to provide cell-type-specific cues to allow for cell proliferation and form a construct that mimics the skin environment. © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

McAlvin J.B.,Harvard University | McAlvin J.B.,Laboratory for Biomaterials and Drug Delivery | McAlvin J.B.,Harvard Massachusetts Institute of Technology Division of Health Sciences and Technology | Reznor G.,Laboratory for Biomaterials and Drug Delivery | And 5 more authors.
Anesthesia and Analgesia | Year: 2013

BACKGROUND: Local tissue injury from sustained-release formulations for local anesthetics can be severe. There is considerable variability in reporting of that injury. We investigated the influence of the intrinsic myotoxicity of the encapsulated local anesthetic (lidocaine, low; bupivacaine, high) on tissue reaction in rats. METHODS: Cytotoxicity from a range of lidocaine and bupivacaine concentrations was measured in C2C12 myotubes over 6 days. Rats were given sciatic nerve blocks with 4 microparticulate formulations of lidocaine and bupivacaine: 10% (w/w) lidocaine poly(lactic-co-glycolic) acid (PLGA), 10% (w/w) bupivacaine PLGA, 50% (w/w) lidocaine PLGA, and 50% (w/w) bupivacaine PLGA. Effectiveness of nerve blockade was assessed by a modified hotplate test and weightbearing measurements. Myotoxicity was scored in histologic sections of injection sites. Bupivacaine and lidocaine release kinetics from the particles were measured. RESULTS: Median sensory blockade duration for 50% (w/w) lidocaine was 255 (90-540) minutes versus 840 (277-1215) minutes for 50% (w/w) bupivacaine (P = 0.056). All microparticulate formulations resulted in myotoxicity. The choice of local anesthetic did not influence the severity of myotoxicity. Median myotoxicity scores for 50% (w/w) lidocaine compared with 50% (w/w) bupivacaine at 4 days were 3.4 (2.1-4.2) vs 3.3 (2.9-3.5) (P = 0.44) and at 14 days 1.9 (1.8-2.4) vs 1.7 (1.3-1.9) (P = 0.23), respectively. CONCLUSIONS: Lidocaine and bupivacaine PLGA microspheres resulted in similar degrees of myotoxicity, irrespective of drug loading. Intrinsic myotoxicity did not predict tissue injury from sustained release of these anesthetics. Caution is warranted in the use of such devices near muscle and nerve. Copyright © 2013 International Anesthesia Research Society.

Hudson S.P.,Massachusetts Institute of Technology | Hudson S.P.,University of Limerick | Langer R.,Massachusetts Institute of Technology | Fink G.R.,Whitehead Institute For Biomedical Research | Kohane D.S.,Laboratory for Biomaterials and Drug Delivery
Biomaterials | Year: 2010

Invasive fungal infections can be devastating, particularly in immunocompromised patients, and difficult to treat with systemic drugs. Furthermore, systemic administration of those medications can have severe side effects. We have developed an injectable local antifungal treatment for direct administration into existing or potential sites of fungal infection. Amphotericin B (AmB), a hydrophobic, potent, and broad-spectrum antifungal agent, was rendered water-soluble by conjugation to a dextran-aldehyde polymer. The dextran-aldehyde-AmB conjugate retained antifungal efficacy against Candida albicans. Mixing carboxymethylcellulose-hydrazide with dextran-aldehyde formed a gel that cross-linked in situ by formation of hydrazone bonds. The gel provided in vitro release of antifungal activity for 11 days, and contact with the gel killed Candida for three weeks. There was no apparent tissue toxicity in the murine peritoneum and the gel caused no adhesions. Gels produced by entrapment of a suspension of AmB in CMC-dextran without conjugation of drug to polymers did not release fungicidal activity, but did kill on contact. Injectable systems of these types, containing soluble or insoluble drug formulations, could be useful for treatment of local antifungal infections, with or without concurrent systemic therapy. © 2009 Elsevier Ltd. All rights reserved.

News Article | August 30, 2016

A contact lens designed to deliver medication gradually to the eye could improve outcomes for patients with conditions requiring treatment with eye drops, which are often imprecise and difficult to self-administer. In a study published online in Ophthalmology, a team of researchers have shown that a novel contact lens-based system, which uses a strategically placed drug polymer film to deliver medication gradually to the eye, is at least as effective, and possibly more so, as daily latanoprost eye drops in a pre-clinical model for glaucoma. "We found that a lower-dose contact lens delivered the same amount of pressure reduction as the latanoprost drops, and a higher-dose lens, interestingly enough, had better pressure reduction than the drops in our small study," said first author Joseph B. Ciolino, M.D., an ophthalmologist at Massachusetts Eye and Ear and an Assistant Professor of Ophthalmology at Harvard Medical School. "Based on our preliminary data, the lenses have not only the potential to improve compliance for patients, but also the potential of providing better pressure reduction than the drops." Glaucoma is the leading cause of irreversible blindness in the world. While there is no cure for glaucoma, ocular medications aim to lower pressure in the eye with the goal of preventing vision loss. Currently, the medications are delivered as eye drops, which sometimes cause stinging and burning, can be difficult to self-administer and are subsequently associated with poor patient compliance, with some studies suggesting that compliance is as low as 50 percent. "This promising delivery system removes the burden of administration from the patient and ensures consistent delivery of medication to the eye, eliminating the ongoing concern of patient compliance with dosing," said Janet B. Serle, M.D., a glaucoma specialist at Icahn School of Medicine at Mount Sinai. Contact lenses have been studied as a means of ocular drug delivery for nearly 50 years, yet many such lenses are ineffective because they dispense the drug too quickly. The authors of the Ophthalmology study designed the contact lens to allow for a more controlled drug release. The researchers had previously shown in a 2014 study that the lens is capable of delivering medication continuously for one month. The researchers designed a novel contact lens that contains a thin film of drug-encapsulated polymers in the periphery. The drug-polymer film slows the drug coming out of the lens. Because the drug film is on the periphery, the center of the lens is clear, allowing for normal visual acuity, breathability and hydration. The lenses can be made with no refractive power or with the ability to correct the refractive error in nearsighted or farsighted eyes. "Instead of taking a contact lens and allowing it to absorb a drug and release it quickly, our lens uses a polymer film to house the drug, and the film has a large ratio of surface area to volume, allowing the drug to release more slowly," said senior author Daniel S. Kohane, M.D., Ph.D., director of the Laboratory for Biomaterials and Drug Delivery at Boston Children's Hospital. In a study supported by a grant from the Boston Children's Hospital Technology and Innovation Development Office, the effect of this drug eluting contact lens was assessed in four glaucomatous monkeys. The researchers showed that the contact lens with lower doses of latanoprost delivers the same amount of eye pressure reduction as the eye drop version of the medication. The lenses delivering higher doses of latanoprost had better pressure reduction than the drops. Further study is needed to confirm the finding in the higher-dose lenses. The researchers are currently designing clinical trials to determine safety and efficacy of the lenses in humans. "If we can address the problem of compliance, we may help patients adhere to the therapy necessary to maintain vision in diseases like glaucoma, saving millions from preventable blindness," said Dr. Ciolino. "This study also raises the possibility that we may have an option for glaucoma that's more effective than what we have today."

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