Massachusetts Institute of Technology

Children's Medical Center Corporation

The Brigham and Women's Hospital, Inc.

The Charles Stark Draper Laboratory, Inc.

Other

University of Pittsburgh

Northeastern University

US Government As Represented by the Secretary of the Army

Linda G Griffith

Robert Samuel Langer

Darrell J Irvine

Joseph P Vacanti

David L Trumper

Antonios Georgios Mikos

Anne M Mayes

Pallab Banerjee

Steven R Tannenbaum

Samuel Walker Inman

Georgios Sarakinos

Terry D Johnson

Jeffrey T Borenstein

Richard Theodore Lee

Mark Joseph Mescher

Douglas A Lauffenburger

Joseph D Cuiffi

Anilkumar Harapanahalli Achyuta

Karel Domansky

Collin Edington

Gaurav Rohatgi

Duncan Freake

Luis Soenksen

Miles Aaron Miller

Luis M Alvarez

Anthony Atala

Michael John Cima

Charles Alfred Vacanti

Scott Robert Brown

Alan H Wells

Frank B Gertler

Keith T Paige

Jill K Sherwood

Timothy Kassis

Transon Van Nguyen

Madeleine J Oudin

Brij Mohan Bhushan

Ravindra Kodihalli

Steven M Jay

Mohan Brij Bhushan

Yadir Guerrero

Caroline Chopko Ahrens

Mark J Powers

Linda Stockdale

Charles D Thompson

Jaime Rivera

Collin D J Edington

Victor Hernandez-Gordillo

Emily C Suter

Christi Dionne Cook

Evan L Chiswick

Rebecca Lyn Carrier

Aaron Samuel Meyer

Luis Alvarez

Synthetic hydrogels for organogenesis support organogenesis from mammalian cells, including human cells. The synthetic hydrogels typically include a network of crosslinked branched biodegradable polymers. A portion of the branches of the branched biodegradable polymers are linked to binders which are generally synthetic peptides for cell and extracellular matrix attachment. The hydrogels may include an inhibitor of apoptosis. The synthetic hydrogels with the synthetic binders typically do not interfere with cellular, proteomic, genetic, and/or transcriptome analyses of organoids formed in the hydrogel. The synthetic hydrogels may be subject to on-demand dissolution to provide intact organoids substantially free of hydrogel polymers. Also provided are methods of making the synthetic hydrogels and methods of using the synthetic hydrogels for organogenesis.

Synthetic hydrogels for organogenesis

Fluidic multiwell bioreactors are provided as a microphysiological platform for in vitro investigation of multi-organ crosstalks for an extended period of time of at least weeks and months. The disclosed platform is featured with one or more improvements over existing bioreactors, including on-board pumping for pneumatically driven fluid flow, a redesigned spillway for self-leveling from source to sink, a non-contact built-in fluid level sensing device, precise control on fluid flow profile and partitioning, and facile reconfigurations such as daisy chaining and multilayer stacking. The platform supports the culture of multiple organs in a microphysiological, interacted systems, suitable for a wide range of biomedical applications including systemic toxicity studies and physiology-based pharmacokinetic and pharmacodynamic predictions. A process to fabricate the disclosed bioreactors is also provided.

Modular organ microphysiological system with integrated pumping, leveling, and sensing

Proteases regulate a wide range of normal cellular functions where dysregulated activity is observed in various diseases. Compositions and methods use protease activity multiplexed bead-based immunoassays to profile protease activity. This platform technology integrates protease activity measurements with total protein quantification techniques. It represents a significant improvement over existing detection techniques by allowing for multiplexed, sensitive active protease measurements in complex biological samples. Exemplary multiplexed detections are realized in a single assay using a minute sample amount (e.g., 5 &#x3bc;l) for active recombinant MMP-1, -2, -3, -7, 9, and 12 and those same MMPs in cell culture supernatant, menstrual fluid effluent, and peritoneal aspirates. This multiplexed platform achieves high level of sensitivities equal to or better than existing leading single-plex detection strategies. It also allows for high throughput screening to identify inhibitors of proteases in complex, donor-derived samples.

Compositions and multiplex assays for characterizing active proteases and their inhibitors

The systems and methods disclosed herein are generally related to a cell culture system. More particularly, the systems and methods enable the culturing and interconnecting of a plurality of tissue types in a biomimetic environment. By culturing organ specific tissue types within a biomimetic environment and interconnecting each of the organ systems in a physiologically meaningful way, experiments can be conducted on in vitro cells that substantially mimic the responses of in vivo cell populations. In some implementations, the system is used to monitor how organ systems respond to agents such as toxins or medications. The system enables the precise and controlled delivery of these agents, which, in some implementations, enables the biomimetic dosing of drugs in humans to be mimicked.

Modular platform for tissue integrated cell culture

The invention is directed to a composition comprising all or a portion of a beta-tricalcium phosphate (&#x3b2;-TCP) bound to all or a portion of a &#x3b2;-TCP binding peptide and methods of use thereof.

Tricalcium phosphate binding peptides and uses thereof

A device for controlling apical flow to a cell culture includes an apical insert that defines at least one inlet channel extending from an inlet port to an apical feed port and at least one outlet channel extending from an apical effluent port to an outlet port. The apical insert includes a projecting portion configured to extend into a cell culture insert to a depth that is less than a depth of the cell culture insert, and a contact surface configured to maintain a spatial relationship between the projecting portion and the cell culture insert.

Device for controlled apical flow in cell culture inserts

Methods, compounds and kits relating to treating cancer, reducing kinase inhibitor or resistance, and reducing or preventing diminished ectodomain shedding are described.

Methods of treating cancer with a combination of selected MEK1/2 and AXL inhibitors

Modular platform for multi-tissue integrated cell culture

Provided herein are ligand dimers, compositions thereof, as well as methods of their use. The ligand dimers provided can comprise at least one ligand to a Her receptor and can be used to force dimerization of specific receptor pairs. The forced dimerization of specific receptor pairs can be used to control (e.g., promote or inhibit) signaling, and, therefore, the ligand dimers provided can also be used in various forms of treatment in which such signaling control is beneficial to a subject. It follows that methods for controlling signaling are provided as are various methods of treatment.

Compositions of and methods of using ligand dimers

The invention provides methods and compositions for reducing, preventing or reversing cardio toxicity side effects associated with certain therapeutic agents. The invention also provides methods and compositions for treating heart dysfunction including heart failure, and for reversing the effects of myocardial infarction. The various aspects of the invention involve the use of ligand dimers, such as neuregulin dimers, that selectively induce the dimerization of certain EGF receptors in cardiac tissue.

Methods for cardioprotection and cardioregeneration with dimers of EGF family ligands

A system has been constructed that recapitulate the features of a capillary bed through normal human tissue. The system facilitates perfusion of three-dimensional (3D) cell monocultures and heterotypic cell co-cultures at the length scale of the capillary bed. A major feature is that the system can be utilized within a 'multiwell plate' format amenable to high-throughput assays compatible with the type of robotics commonly used in pharmaceutical development. The system provides a means to conduct assays for toxicology and metabolism and as a model for human diseases such as hepatic diseases, including hepatitis, exposure-related pathologies, and cancer. Cancer applications include primary liver cancer as well as metastases. The system can also be used as a means of testing gene therapy approaches for treating disease and inborn genetic defects.

Perfused three-dimensional cell/tissue disease models

Polymeric materials are used to make a pliable, non-toxic, injectable porous template for vascular ingrowth. The pore size, usually between approximately 100 and 300 microns, allows vascular and connective tissue ingrowth throughout approximately 10 to 90% of the matrix following implantation, and the injection of cells uniformly throughout the implanted matrix without damage to the cells or patient. The introduced cells attach to the connective tissue within the matrix and are fed by the blood vessels. The preferred material for forming the matrix or support structure is a biocompatible synthetic polymer which degrades in a controlled manner by hydrolysis into harmless metabolites, for example, polyglycolic acid, polylactic acid, polyorthoester, polyanhydride, or copolymers thereof. The rate of tissue ingrowth increases as the porosity and/or the pore size of the implanted devices increases. The time required for the tissue to fill the device depends on the polymer crystallinity and is less for amorphous polymers versus semicrystalline polymers. The vascularity of the advancing tissue is consistent with time and independent of the biomaterial composition and morphology.

Method of forming a tissue structure by introducing cells into an implanted matrix

Slowly polymerizing polysaccharide hydrogels have been demonstrated to be useful as a means of delivering large numbers of isolated cells via injection. The gels promote engraftment and provide three dimensional templates for new cell growth. The resulting tissue is similar in composition and histology to naturally occurring tissue. This method can be used for a variety of reconstructive procedures, including custom molding of cell implants to reconstruct three dimensional tissue defects, as well as implantation of tissues generally.

Injectable composition containing crosslinkable material and cells for forming animal tissue

Porous biodegradable polymeric materials for cell transplantation

Growing community of inventors

Cambridge, MA, United States of America

Linda G Griffith