Tissue Engineering Laboratories

Boston, MA, United States

Tissue Engineering Laboratories

Boston, MA, United States
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Shah N.J.,Massachusetts Institute of Technology | Hyder M.N.,Massachusetts Institute of Technology | Quadir M.A.,Massachusetts Institute of Technology | Courchesne N.-M.D.,Massachusetts Institute of Technology | And 5 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound. Here, we report an approach for bone repair using a polyelectrolye multilayer coating carrying as little as 200 ng of bone morphogenetic protein-2 and platelet-derived growth factor-BB that were eluted over readily adapted time scales to induce rapid bone repair. Based on electrostatic interactions between the polymer multilayers and growth factors alone, we sustained mitogenic and osteogenic signals with these growth factors in an easily tunable and controlled manner to direct endogenous cell function. To prove the role of this adaptive release system, we applied the polyelectrolyte coating on a well-studied biodegradable poly(lactic-co-glycolic acid) support membrane. The released growth factors directed cellular processes to induce bone repair in a critical-size rat calvaria model. The released growth factors promoted local bone formation that bridged a critical-size defect in the calvaria as early as 2 wk after implantation. Mature, mechanically competent bone regenerated the native calvaria form. Such an approach could be clinically useful and has significant benefits as a synthetic, off-the-shelf, cell-free option for bone tissue repair and restoration.


Toh W.S.,Tissue Engineering Laboratories | Toh W.S.,Harvard University | Spector M.,Tissue Engineering Laboratories | Spector M.,Harvard University | And 2 more authors.
Molecular Pharmaceutics | Year: 2011

Articular cartilage injuries are one of the most challenging problems in musculoskeletal medicine due to the poor intrinsic regenerative capacity of this tissue. The lack of efficient treatment modalities motivates research into tissue engineering: combining cells, biomaterials mimicking extracellular matrix (scaffolds) and microenvironmental signaling cues. The aim of this review is to focus on the use of biomaterials as delivery systems for microenvironmental cues in relation to their applications for treatment of cartilage defects. The latest advances in cartilage tissue engineering and regeneration are critically reviewed to demonstrate an outline of challenges toward biomaterial-based approaches of cartilage regeneration. © 2011 American Chemical Society.


Toh W.S.,National University of Singapore | Toh W.S.,Tissue Engineering Laboratories | Toh W.S.,Harvard University | Lee E.H.,National University of Singapore | Cao T.,National University of Singapore
Stem Cell Reviews and Reports | Year: 2011

The current surgical intervention of using autologous chondrocyte implantation (ACI) for cartilage repair is associated with several problems such as donor site morbidity, de-differentiation upon expansion and fibrocartilage repair following transplantation. This has led to exploration of the use of stem cells as a model for chondrogenic differentiation as well as a potential source of chondrogenic cells for cartilage tissue engineering and repair. Embryonic stem cells (ESCs) are advantageous, due to their unlimited self-renewal and pluripotency, thus representing an immortal cell source that could potentially provide an unlimited supply of chondrogenic cells for both cell and tissue-based therapies and replacements. This review aims to present an overview of emerging trends of using ESCs in cartilage tissue engineering and regenerative medicine. In particular, we will be focusing on ESCs as a promising cell source for cartilage regeneration, the various strategies and approaches employed in chondrogenic differentiation and tissue engineering, the associated outcomes from animal studies, and the challenges that need to be overcome before clinical application is possible. © 2010 Springer Science+Business Media, LLC.


Elias P.Z.,Harvard-MIT Division of Health Sciences and Technology | Elias P.Z.,Tissue Engineering Laboratories | Spector M.,Tissue Engineering Laboratories | Spector M.,Harvard University
Journal of Neuroscience Methods | Year: 2012

Penetrating brain injury (PBI) is a complex central nervous system injury in which mechanical damage to brain parenchyma results in hemorrhage, ischemia, broad areas of necrosis, and eventually cavitation. The permanent loss of brain tissue affords the possibility of treatment using a biomaterial scaffold to fill the lesion site and potentially deliver pharmacological or cellular therapeutic agents. The administration of cellular therapy may be of benefit in both mitigating the secondary injury process and promoting regeneration through replacement of certain cell populations. This study investigated the survival and differentiation of adult rat hippocampal neural progenitor cells delivered by a collagen scaffold in a rat model of PBI. The cell-scaffold construct was implanted 1 week after injury and was observed to remain intact with open pores upon analysis 4 weeks later. Implanted neural progenitors were found to have survived within the scaffold, and also to have migrated into the surrounding brain. Differentiated phenotypes included astrocytes, oligodendrocytes, vascular endothelial cells, and possibly macrophages. The demonstrated multipotency of this cell population in vivo in the context of traumatic brain injury has implications for regenerative therapies, but additional stimulation appears necessary to promote neuronal differentiation outside normally neurogenic regions. © 2012 Elsevier B.V.


Shah N.J.,Massachusetts Institute of Technology | Hyder Md.N.,Massachusetts Institute of Technology | Moskowitz J.S.,Massachusetts Institute of Technology | Quadir M.A.,Massachusetts Institute of Technology | And 8 more authors.
Science Translational Medicine | Year: 2013

The functional success of a biomedical implant critically depends on its stable bonding with the host tissue. Aseptic implant loosening accounts for more than half of all joint replacement failures. Various materials, including metals and plastic, confer mechanical integrity to the device, but often these materials are not suitable for direct integration with the host tissue, which leads to implant loosening and patient morbidity. We describe a self-assembled, osteogenic, polymer-based conformal coating that promotes stable mechanical fixation of an implant in a surrogate rodent model. A single modular, polymer-based multilayered coating was deposited using a water-based layer-by-layer approach, by which each element was introduced on the surface in nanoscale layers. Osteoconductive hydroxyapatite (HAP) and osteoinductive bone morphogenetic protein-2 (BMP-2) contained within the nanostructured coating acted synergistically to induce osteoblastic differentiation of endogenous progenitor cells within the bone marrow, without indications of a foreign body response. The tuned release of BMP-2, controlled by a hydrolytically degradable poly(β-amino ester), was essential for tissue regeneration, and in the presence of HAP, the modular coating encouraged the direct deposition of highly cohesive trabecular bone on the implant surface. In vivo, the bone-implant interfacial tensile strength was significantly higher than standard bioactive bone cement, did not fracture at the interface, and had long-term stability. Collectively, these results suggest that the multilayered coating system promotes biological fixation of orthopedic and dental implants to improve surgical outcomes by preventing loosening and premature failure. Copyright © 2013 by the American Association for the Advancement of Science; all rights reserved.


Lim T.C.,Harvard-MIT Division of Health Sciences and Technology | Lim T.C.,Tissue Engineering Laboratories | Toh W.S.,Tissue Engineering Laboratories | Toh W.S.,Harvard University | And 5 more authors.
Biomaterials | Year: 2012

Transplanted or endogenous neural stem cells often lack appropriate matrix in cavitary lesions in the central nervous system. In this study, gelatin-hydroxyphenylpropionic acid (Gtn-HPA), which could be enzymatically crosslinked with independent tuning of crosslinking degree and gelation rate, was explored as an injectable hydrogel for adult neural stem cells (aNSCs). The storage modulus of Gtn-HPA could be tuned (449-1717 Pa) to approximate adult brain tissue. Gtn-HPA was cytocompatible with aNSCs (yielding high viability >93%) and promoted aNSC adhesion. Gtn-HPA demonstrated a crosslinking-based approach for preconditioning aNSCs and increased the resistance of aNSCs to oxidative stress, improving their viability from 8-15% to 84% when challenged with 500 μM H 2O 2. In addition, Gtn-HPA was able to modulate proliferation and migration of aNSCs in relation to the crosslinking degree. Finally, Gtn-HPA exhibited bias for neuronal cells. In mixed differentiation conditions, Gtn-HPA increased the proportion of aNSCs expressing neuronal marker β-tubulin III to a greater extent than that for astrocytic marker glial fibrillary acidic protein, indicating an enhancement in differentiation towards neuronal lineage. Between neuronal and astrocytic differentiation conditions, Gtn-HPA also selected for higher survival in the former. Overall, Gtn-HPA hydrogels are promising injectable matrices for supporting and influencing aNSCs in ways that may be beneficial for brain tissue regeneration after injuries. © 2012 Elsevier Ltd.


Cholas R.,Harvard-MIT Division of Health Sciences and Technology | Cholas R.,Tissue Engineering Laboratories | Hsu H.-P.,Tissue Engineering Laboratories | Hsu H.-P.,Harvard University | And 2 more authors.
Tissue Engineering - Part A | Year: 2012

A multifaceted therapeutic approach involving biomaterial scaffolds, neurotrophic factors, exogenous cells, and antagonists to axon growth inhibitors may ultimately prove necessary for the treatment of defects resulting from spinal cord injury (SCI). The objective of this study was to begin to lay the groundwork for such strategies by implanting type I collagen scaffolds alone and incorporating individually a soluble Nogo receptor, chondroitinase ABC (ChABC), and mesenchymal stem cells (MSCs) into a standardized 3-mm-long hemiresection defect in the rat spinal cord. Statistically significant improvement in hindlimb motor function between the first and fourth weeks post-SCI was recorded for the scaffold-alone group and for the ChABC and MSC groups, but not the control group. Four weeks post-SCI, the scaffolds appeared intact with open pores, which were infiltrated with host cells. Of note is that in some cases, a few growth-associated protein 43 (GAP-43)-positive axons were seen reaching the center of the scaffold in the scaffold-alone and ChABC groups, but not in control animals. Angiogenic cells were prevalent in the scaffolds; however, the number of both macrophages and angiogenic cells in the scaffolds was significantly less than in the control lesion at 4 weeks. The results lay the foundation for future dose-response studies and to further investigate a range of therapeutic agents to enhance the regenerative response in SCI. © Copyright 2012, Mary Ann Liebert, Inc.


Cholas R.H.,Harvard-MIT Division of Health Sciences and Technology | Cholas R.H.,Tissue Engineering Laboratories | Hsu H.-P.,Tissue Engineering Laboratories | Hsu H.-P.,Harvard University | And 2 more authors.
Biomaterials | Year: 2012

Prior work demonstrated the improvement of peripheral nerve regeneration in gaps implanted with collagen scaffold-filled collagen tubes, compared with nerve autografts, and the promise of such implants for treating gaps in spinal cord injury (SCI) in rats. The objective of this study was to investigate collagen implants alone and incorporating select therapeutic agents in a 5-mm full-resection gap model in the rat spinal cord. Two studies were performed, one with a 6-week time point and one with a 2-week time point. For the 6-week study the groups included: (1) untreated control, (2) dehydrothermally (DHT)-cross-linked collagen scaffold, (3) DHT-cross-linked collagen scaffold seeded with adult rat neural stem cells (NSCs), and (4) DHT-cross-linked collagen scaffold incorporating plasmid encoding glial cell line-derived neurotropic factor (pGDNF). The 2-week study groups were: (1) nontreated control, (2) DHT-cross-linked collagen scaffold; (3) DHT-cross-linked collagen scaffold containing laminin; and (4) carbodiimide-cross-linked collagen scaffold containing laminin. The tissue filling the defect of all groups at 6 weeks was largely composed of fibrous scar; however, the tissue was generally more favorably aligned with the long axis of the spinal cord in all of the treatment groups, but not in the control group. Quantification of the percentage of animals per group containing cystic cavities in the defect showed a trend toward fewer rats with cysts in the groups in which the scaffolds were implanted compared to control. All of the collagen implants were clearly visible and mostly intact after 2 weeks. A band of fibrous tissue filling the control gaps was not seen in the collagen implant groups. In all of the groups there was a narrowing of the spinal canal within the gap as a result of surrounding soft tissue collapse into the defect. The narrowing of the spinal canal occurred to a greater extent in the control and DHT scaffold alone groups compared to the DHT scaffold/laminin and EDAC scaffold/laminin groups. Collagen biomaterials can be useful in the treatment of SCI to: favorably align the reparative tissue with the long axis of the spinal cord; potentially reduce the formation of fluid-filled cysts; serve as a delivery vehicle for NSCs and the gene for GDNF; and impede the collapse of musculature and connective tissue into the defect. © 2011 Elsevier Ltd.


Elias P.Z.,Harvard-MIT Division of Health Sciences and Technology | Elias P.Z.,Tissue Engineering Laboratories | Spector M.,Tissue Engineering Laboratories | Spector M.,Harvard University
Journal of Neurotrauma | Year: 2012

Penetrating brain injury (PBI) encountered in both the military and civilian sectors results in high morbidity and mortality due to the absence of effective treatment options for survivors of the initial trauma. Developing therapies for such injuries requires a better understanding of the complex pathology involved when projectiles enter the skull and disrupt the brain parenchyma. This study presents a histological characterization of bilateral PBI using a relatively new injury model in the rat, and also investigates the implantation of a collagen scaffold into the PBI lesion as a potential treatment option. At 1 week post-PBI, the lesion was characterized by dense macrophage infiltration, evolving astrogliosis, hypervascularity, and an absence of viable neurons, oligodendrocytes, and myelinated axons. Histomorphometric analysis revealed that the PBI lesion volume expanded by 29% between 1 week and 5 weeks post-injury, resulting in formation of a large acellular cavity. Immunohistochemistry showed a decrease in the presence of CD68-positive macrophages from 1 to 5 weeks post-PBI as the necrotic tissue in the lesion was cleared, while persistent glial scarring remained in the form of upregulated GFAP expression surrounding the PBI cavity. Implanted type I collagen scaffolds remained intact with open pores after time periods of 1 week and 4 weeks in vivo, and were found to be sparsely infiltrated with macrophages, astrocytes, and endothelial cells. Collagen scaffolds appear to be an appropriate delivery vehicle for cellular and pharmacological therapeutic agents in future studies of PBI. © Copyright 2012, Mary Ann Liebert, Inc.


Elias P.Z.,Tissue Engineering Laboratories | Elias P.Z.,Harvard-MIT Division of Health Sciences and Technology | Spector M.,Tissue Engineering Laboratories | Spector M.,Harvard University
Journal of the Mechanical Behavior of Biomedical Materials | Year: 2012

In the field of tissue engineering and regenerative medicine for the central nervous system, therapeutic strategies may involve implantation of biomaterial scaffolds into the brain. An understanding of the relationship between the brain and the scaffold mechanical properties can help in the selection of a safe and effective biomaterial. This research demonstrates the use of indentation testing along with viscoelastic modeling to characterize and compare mechanical properties of in situ rat cerebral cortex and collagen scaffolds of varying collagen concentration. The stress-relaxation solution for indentation of a viscoelastic material was derived based on a five-element Maxwell model and use of the correspondence principle. Applying the model to experimental stress-relaxation data, the brain was characterized by three shear moduli G1=1.6±0.10kPa, G2=2.0±0.15kPa, G3=1.8±0.20kPa, and two viscosities n2=11.0±0.44kPa{dot operator}s, n3=148.7±6.70kPa{dot operator}s, with corresponding relaxation time constants τ1=5.7±0.3s and τ2=88.4±7.6s. The brain showed average relaxation of 74% from its peak force during loading to an approximately asymptotic force over a 5 minute hold at constant displacement. Collagen scaffolds generally showed increasing trends in the shear moduli, viscosities, and percentage relaxation with increasing collagen concentration. While the brain had similar stiffness to the 1.0% collagen scaffold during the loading phase, the brain's relaxation behavior was distinct from all of the scaffolds. Similarities and differences between the mechanical behavior of the brain and collagen scaffolds of varying collagen concentration are discussed in relation to application of biomaterials for regenerative medicine. © 2012 Elsevier Ltd.

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