Manav Mehta
Harvard University, SEAS Harvard, Department Member
Research Interests: Mechanics, Sex, Fracture, Bone Healing, Medicine, and 5 moreAge, Geschlecht, Alter, Callus, and Bone Defect
Research Interests: Electrical Engineering, Electronic Engineering, Chemical Engineering, Civil Engineering, Control Systems Engineering, and 15 moreAerospace Engineering, Biomedical Engineering, Computer Engineering, Biomaterials, Electrochemistry, Autonomous Robotics, Cognitive Robotics, Electrokinetics in Microfluidics, Educational Robotics, Automation and robotics in Construction, Alfred Gell, BCG matrix, Acrylic Acid, Biocompatible Materials, and Cryogels(Aerospace Engineering, Biomedical Engineering, Computer Engineering, Biomaterials, Electrochemistry, Autonomous Robotics, Cognitive Robotics, Electrokinetics in Microfluidics, Educational Robotics, Automation and robotics in Construction, Alfred Gell, BCG matrix, Acrylic Acid, Biocompatible Materials, and Cryogels)
(Aerospace Engineering, Biomedical Engineering, Computer Engineering, Biomaterials, Electrochemistry, Autonomous Robotics, Cognitive Robotics, Electrokinetics in Microfluidics, Educational Robotics, Automation and robotics in Construction, Alfred Gell, BCG matrix, Acrylic Acid, Biocompatible Materials, and Cryogels)
ABSTRACTAdult bone marrow derived mesenchymal stem cells (MSCs) represent an important source of cells for tissue regeneration. Control of MSC migration and homing is still unclear. The goal of this study was to identify potent... more
ABSTRACTAdult bone marrow derived mesenchymal stem cells (MSCs) represent an important source of cells for tissue regeneration. Control of MSC migration and homing is still unclear. The goal of this study was to identify potent chemoattractants for MSCs and characterize MSC chemotaxis using a microfluidic device as a model system and assay platform. The three chemokines compared in this study were CXCL7, CXCL12, and AMD 3100.Microfluidic devices made of polydimethysiloxane (PDMS) were fabricated by soft lithography techniques and designed to generate a stable linear chemokine gradient. Cell movements in response to the gradient were captured by timelapse photos and tracked over 24 hours. Chemokine potency was measured via several chemotaxis parameters including: velocity in the direction of interest (V), center of mass (Mend), forward migration indice (YFMI). The migratory paths of the cells were mapped onto a displacement plot and compared.The following results were measured in the...
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Various therapeutic strategies that aim to influence clinical outcome after severe skeletal muscle trauma have been considered. One such method, the local transplantation of stem cells, has been shown to improve tissue regeneration. The... more
Various therapeutic strategies that aim to influence clinical outcome after severe skeletal muscle trauma have been considered. One such method, the local transplantation of stem cells, has been shown to improve tissue regeneration. The number of cells required for successful regeneration, however, remains unclear. The aim of this study was therefore to examine the correlation between the number of transplanted bone marrow-derived mesenchymal stem cells (MSCs) and the resulting muscle function. One week after inducing an open crush trauma in 34 female Sprague Dawley rats, increasing quantities of autologous MSCs (0.1 x 10(6), 1 x 10(6), 2.5 x 10(6), and 10 x 10(6) cells) or saline solution (control group) were transplanted into the left soleus muscle of the rat hind limb. At 4 weeks posttrauma, the outcome was assessed by measuring muscle contraction forces following an indirect fast twitch and tetanic stimulation. A logarithmic dose-response relationship was observed for both maximum twitch and tetanic contraction forces (R(2) = 0.9 for fast twitch [p = 0.004]; R(2) = 0.87 [p = 0.002] for tetanic contraction). The transplantation of 10 x 10(6) cells resulted in the most pronounced improvement of muscle force. MSC therapy represents a promising new tool for the treatment of skeletal muscle trauma that shows potential for aiding in the prevention of severe functional deficiencies. The logarithmic dose-response relationship demonstrates the association between the number of transplanted cells and the resulting muscle forces, as well as the amount of MSCs required for promoting muscular regeneration.
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Various therapeutic strategies that aim to influence clinical outcome after severe skeletal muscle trauma have been considered. One such method, the local transplantation of stem cells, has been shown to improve tissue regeneration. The... more
Various therapeutic strategies that aim to influence clinical outcome after severe skeletal muscle trauma have been considered. One such method, the local transplantation of stem cells, has been shown to improve tissue regeneration. The number of cells required for successful regeneration, however, remains unclear. The aim of this study was therefore to examine the correlation between the number of transplanted bone marrow-derived mesenchymal stem cells (MSCs) and the resulting muscle function. One week after inducing an open crush trauma in 34 female Sprague Dawley rats, increasing quantities of autologous MSCs (0.1 x 10(6), 1 x 10(6), 2.5 x 10(6), and 10 x 10(6) cells) or saline solution (control group) were transplanted into the left soleus muscle of the rat hind limb. At 4 weeks posttrauma, the outcome was assessed by measuring muscle contraction forces following an indirect fast twitch and tetanic stimulation. A logarithmic dose-response relationship was observed for both maximum twitch and tetanic contraction forces (R(2) = 0.9 for fast twitch [p = 0.004]; R(2) = 0.87 [p = 0.002] for tetanic contraction). The transplantation of 10 x 10(6) cells resulted in the most pronounced improvement of muscle force. MSC therapy represents a promising new tool for the treatment of skeletal muscle trauma that shows potential for aiding in the prevention of severe functional deficiencies. The logarithmic dose-response relationship demonstrates the association between the number of transplanted cells and the resulting muscle forces, as well as the amount of MSCs required for promoting muscular regeneration.
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This review aims to address the current limitations in biomaterial scaffold-based treatment strategies for bone defect healing and suggests new, alternative approaches that merit further investigation. The question of whether the... more
This review aims to address the current limitations in biomaterial scaffold-based treatment strategies for bone defect healing and suggests new, alternative approaches that merit further investigation. The question of whether the biomaterial scaffold properties should mimic the natural extracellular matrix of mature tissue or some phase of the dynamic range of tissues observed during the healing process is discussed. Additionally, the authors advocate for a biomimetic approach, which uses the endogenous secondary fracture ...
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This review aims to address the current limitations in biomaterial scaffold-based treatment strategies for bone defect healing and suggests new, alternative approaches that merit further investigation. The question of whether the... more
This review aims to address the current limitations in biomaterial scaffold-based treatment strategies for bone defect healing and suggests new, alternative approaches that merit further investigation. The question of whether the biomaterial scaffold properties should mimic the natural extracellular matrix of mature tissue or some phase of the dynamic range of tissues observed during the healing process is discussed. Additionally, the authors advocate for a biomimetic approach, which uses the endogenous secondary fracture ...
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A polycaprolactone-tricalcium phosphate scaffold with recombinant human BMP-7 heals critical-sized bone defects in sheep.
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Research Interests: Surgery, Biomechanics, Prosthesis, Medicine, Finite Element Analysis, and 15 moreHumans, Computer Simulation, Femur, Clinical Sciences, Mechanical Stress, And, Implant, Orthopaedic Surgery, SURGICAL TECHNIQUE, Computer Modelling, prosthesis Design, Tensile Strength, Biomechanical Phenomena, Reoperation, and Hip Joint
Mechanical conditions have a significant influence on the biological processes of bone healing. Small animal models that allow controlling the mechanical environment of fracture and bone defect healing are needed. The aim of this study... more
Mechanical conditions have a significant influence on the biological processes of bone healing. Small animal models that allow controlling the mechanical environment of fracture and bone defect healing are needed. The aim of this study was to develop a new animal model that allows to reliably control the mechanical environment in fracture and bone defect healing in rats using different implant materials. An external fixator was designed and mounted in vitro to rat femurs using four Kirschner-wires (titanium (T) or steel (S)) of 1.2 mm diameter. The specimens were distracted to a gap of 1.5mm. Axial and torsional stiffness of the device was tested increasing the offset (distance between bone and fixator crossbar) from 5 to 15 mm. In vivo performance (well-being, infection, breaking of wires and bone healing) was evaluated in four groups of 24 Sprague-Dawley rats varying in offset (7.5 and 15 mm) and implant material (S/T) over 6 weeks. Torsional and axial stiffness were higher in steel compared to titanium setups. A decrease in all configurations was observed by increasing the offset. The offset 7.5 mm showed a significantly higher torsional (S: p<0.01, T: p<0.001) and axial in vitro stiffness (S: p<0.001, T: p<0.001) compared to 15 mm offset of the fixator. Although in vitro designed to be different in mechanical stiffness, no difference was found between the groups regarding complication rate. The overall-complication rate was 5.2%. In conclusion, we were able to establish a small animal model for bone defect healing which allows modeling the mechanical conditions at the defect site in a defined manner.
Research Interests: Mechanical Engineering, Materials Science, Mechanics, Biomedical Engineering, Biomechanics, and 15 moreMedicine, Female, Animals, Animal Model, Fracture Healing, Bone Defects, Device, Mechanical Stress, Rats, Biological Process, Elastic Modulus, Fracture Fixation, Equipment Design, Equipment Failure Analysis, and Femoral Fractures
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Fracture healing is a unique biologic process starting with an initial inflammatory response. As in other regenerative processes, bone and the immune system interact closely during fracture healing. This project was aimed at further... more
Fracture healing is a unique biologic process starting with an initial inflammatory response. As in other regenerative processes, bone and the immune system interact closely during fracture healing. This project was aimed at further elucidating how the host immune system ...
Research Interests: Engineering, Artificial Immune Systems, Cytokines, Inflammation, Medicine, and 15 moreBiological Sciences, Cell Differentiation, Mice, Bone, Adaptive Immunity, Animals, Male, Fracture Healing, Fracture Healiing, Immune system, Bone Mineral Density, Bone remodeling, B Lymphocytes, Biomechanical Phenomena, and Medical and Health Sciences
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The clinically known importance of patient sex as a major risk factor for compromised bone healing is poorly reflected in animal models. Consequently, the underlying cellular mechanisms remain elusive. Because mesenchymal stem cells... more
The clinically known importance of patient sex as a major risk factor for compromised bone healing is poorly reflected in animal models. Consequently, the underlying cellular mechanisms remain elusive. Because mesenchymal stem cells (MSCs) are postulated to regulate tissue regeneration and give rise to essential differentiated cell types, they may contribute to sex-specific differences in bone healing outcomes. We investigated sex-specific variations in bone healing and associated differences in MSC populations. A 1.5 mm osteotomy gap in the femora of 8 male and 8 female 12-month-old Sprague-Dawley rats was stabilized by an external fixator. Healing was analyzed in terms of biomechanical testing, bridging and callus size over time (radiography at 2, 4, and 6 weeks after surgery), and callus volume and geometry by microCT at final follow-up. MSCs were obtained from bone marrow samples of an age-matched group of 12 animals (6 per gender) and analyzed for numbers of colony-forming units (CFUs) and their capacity to differentiate and proliferate. The proportion of senescent cells was determined by beta-galactosidase staining. Sex-specific differences were indicated by a compromised mechanical competence of the callus in females compared with males (maximum torque at failure, p=0.028). Throughout the follow-up, the cross-sectional area of callus relative to bone was reduced in females (p< or =0.01), and the bridging of callus was delayed (p(2weeks)=0.041). microCT revealed a reduced callus size (p=0.003), mineralization (p=0.003) and polar moment of inertia (p=0.003) in female animals. The female bone marrow contained significantly fewer MSCs, represented by low CFU numbers in both femora and tibiae (p(femur)=0.017, p(tibia)=0.010). Functional characteristics of male and female MSCs were similar. Biomechanically compromised and radiographically delayed bone formation were distinctive in female rats. These differences were concomitant with a reduced number of MSCs, which may be causative for the suboptimal bone healing.
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Research Interests: Engineering, Materials Science, Fracture, Aging, Biological Sciences, and 15 moreAge, Bone, Female, Animals, Bone Density, Fracture Healing, Callus, Fracture Fixation, Blood Vessel, Bone Resorption, Age Groups, Biomechanical Phenomena, cross sectional area, Medical and Health Sciences, and Fractures Bone
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The objectives of this study were to (1) establish a reproducible atrophic non-union model in rats by creation of a segmental femoral bone defect that allows, (2) in-depth characterization of impaired healing, and (3) contrast its healing... more
The objectives of this study were to (1) establish a reproducible atrophic non-union model in rats by creation of a segmental femoral bone defect that allows, (2) in-depth characterization of impaired healing, and (3) contrast its healing patterns to the normal course. Hypothesis was that a 5-mm bone defect in male rats would deviate from uneventful healing patterns and result in an atrophic non-union. A femoral osteotomy was performed in two groups of 12-week-old male rats (1 vs. 5 mm gap) stabilized with an external fixator. Bone healing in these models was evaluated by radiology, biomechanics, and histology at 6 or 8 weeks. The evaluation of the 5-mm group revealed in some cases a delayed rather than a non-union, and therefore, a group of female counterparts was included. The creation of a 5-mm defect in female rats resulted in a reproducible atrophic non-union characterized by sealing of the medullary canal, lack of cartilage formation, and negligible mechanical properties of the callus. In both gap size models, the male subjects showed advanced healing compared to females. This study showed that even under uneventful healing conditions in terms of age and bone defect size, there is a sex-specific advanced healing in male compared to female subjects. Contrary to our initial hypothesis, only the creation of a 5-mm segmental femoral defect in female rats led to a reproducible atrophic non-union. It has been shown that an atrophic non-union exhibits different healing patterns compared to uneventful healing. A total lack of endochondral bone formation, soft tissue prolapse into the defect, and bony closure of the medullary cavity have been shown to occur in the non-union model.
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Bone is one of the few tissues in the human body with high endogenous healing capacity. However, failure of the healing process presents a significant clinical challenge; it is a tremendous burden for the individual and has related health... more
Bone is one of the few tissues in the human body with high endogenous healing capacity. However, failure of the healing process presents a significant clinical challenge; it is a tremendous burden for the individual and has related health and economic consequences. To overcome such healing deficits, various concepts for a local drug delivery to bone have been developed during the last decades. However, in many cases these concepts do not meet the specific requirements of either surgeons who must use these strategies or individual patients who might benefit from them. We describe currently available methods for local drug delivery and their limitations in therapy. Various solutions for drug delivery to bone focusing on clinical applications and intra-operative constraints are discussed and drug delivery by implant coating is highlighted. Finally, a new set of design and performance requirements for intra-operatively customized implant coatings for controlled drug delivery is proposed. In the future, these requirements may improve approaches for local and intra-operative treatment of patients.
Research Interests: Biomaterials, Tissue Engineering, Targeted Drug Delivery, Bone and Antler, Drug delivery, and 15 moreMedicine, Bone Regeneration, Humans, Bone, VEGF, Animals, Drug Delivery Systems, DBM, Biocompatible Materials, Equipment Design, Bone and Bones, Equipment and Supplies, PDGF, Sleeve, and Pharmacology and pharmaceutical sciences
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Influence of prosthesis design and implantation technique on implant stresses after cementless revision THR
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L'invention concerne du materiel et des methodes permettant le traitement d'une fuite pulmonaire. Un peptide comprenant entre environ 7 acides amines et environ 32 acides amines dans une solution peut etre applique a un site... more
L'invention concerne du materiel et des methodes permettant le traitement d'une fuite pulmonaire. Un peptide comprenant entre environ 7 acides amines et environ 32 acides amines dans une solution peut etre applique a un site cible. Une barriere d'hydrogel peut etre placee au niveau du site cible en vue de traiter la fuite pulmonaire.
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Osteonecrosis of the femoral head (ONFH) is a debilitating hip disorder, which often produces a permanent femoral head deformity and osteoarthritis. The local delivery of biological agents capable of stimulating bone healing offer... more
Osteonecrosis of the femoral head (ONFH) is a debilitating hip disorder, which often produces a permanent femoral head deformity and osteoarthritis. The local delivery of biological agents capable of stimulating bone healing offer potential new treatment options for patients with ONFH. Previous studies from our laboratory have shown that a local intra-osseous infusion of bone morphogenic protein-2 (BMP-2) was effective in stimulating new bone formation in a piglet model of ischemic ONFH. However, infusion of BMP-2 solution was associated with unwanted dissemination of BMP-2 out of the femoral head and produced heterotopic ossification in the hip capsule. Injectable hydrogels offer a potential method to control the dissemination of biological molecules in vivo. In the present study, we evaluated the potential of a peptide-based, self-assembling hydrogel called RADA16 to transition from a solution to a gel following infusion into the femoral head, thereby preventing backflow, as well ...
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The use of cementless threaded cups in THA is a well-established treatment. Fractures of the cups are rare complications recorded in individual cases with material defects being discussed as the primary cause. We analyzed three cases of... more
The use of cementless threaded cups in THA is a well-established treatment. Fractures of the cups are rare complications recorded in individual cases with material defects being discussed as the primary cause. We analyzed three cases of fractured cups. Although all three cups were well fixed to existing bone, we observed deficient osseous backing dorsocranially and abrasion particles. There were no signs of femoroacetabular impingement or infection. The cups showed corrosion debris. Scanning electron ...
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In-situ tissue regeneration aims to utilize the body's endogenous healing capacity through the recruitment of host stem or progenitor cells to an injury site. Stromal cell-derived factor-1α (SDF-1α) is widely discussed as a potent... more
In-situ tissue regeneration aims to utilize the body's endogenous healing capacity through the recruitment of host stem or progenitor cells to an injury site. Stromal cell-derived factor-1α (SDF-1α) is widely discussed as a potent chemoattractant. Here we use a cell-free biomaterial-based approach to (i) deliver SDF-1α for the recruitment of endogenous bone marrow-derived stromal cells (BMSC) into a critical-sized segmental femoral defect in rats and to (ii) induce hydrogel stiffness-mediated osteogenic differentiation in-vivo. Ionically crosslinked alginate hydrogels with a stiffness optimized for osteogenic differentiation were used. Fast-degrading porogens were incorporated to impart a macroporous architecture that facilitates host cell invasion. Endogenous cell recruitment to the defect site was successfully triggered through the controlled release of SDF-1α. A trend for increased bone volume fraction (BV/TV) and a significantly higher bone mineral density (BMD) were observe...
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The effectiveness of stem cell therapies has been hampered by cell death and limited control over fate. These problems can be partially circumvented by using macroporous biomaterials that improve the survival of transplanted stem cells... more
The effectiveness of stem cell therapies has been hampered by cell death and limited control over fate. These problems can be partially circumvented by using macroporous biomaterials that improve the survival of transplanted stem cells and provide molecular cues to direct cell phenotype. Stem cell behaviour can also be controlled in vitro by manipulating the elasticity of both porous and non-porous materials, yet translation to therapeutic processes in vivo remains elusive. Here, by developing injectable, void-forming hydrogels that decouple pore formation from elasticity, we show that mesenchymal stem cell (MSC) osteogenesis in vitro, and cell deployment in vitro and in vivo, can be controlled by modifying, respectively, the hydrogel's elastic modulus or its chemistry. When the hydrogels were used to transplant MSCs, the hydrogel's elasticity regulated bone regeneration, with optimal bone formation at 60 kPa. Our findings show that biophysical cues can be harnessed to direc...
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Uncontrolled bleeding from traumatic wounds is a major factor in deaths resulting from military conflict, accidents, disasters and crime. Self-assembling peptide nanofibers have shown superior hemostatic activity, and herein, we elucidate... more
Uncontrolled bleeding from traumatic wounds is a major factor in deaths resulting from military conflict, accidents, disasters and crime. Self-assembling peptide nanofibers have shown superior hemostatic activity, and herein, we elucidate their mechanism by visualizing the formation of nanofiber-based clots that aggregate blood components with a similar morphology to fibrin-based clots. Furthermore, to enhance its direct application to a wound, we developed layer-by-layer assembled thin film coatings onto common materials used for wound dressings-gauze and gelatin sponges. We find these nanofibers elute upon hydration under physiological conditions and generate nanofiber-based clots with blood. After exposure to a range of harsh temperature conditions (-80 to 60 °C) for a week and even 5 months at 60 °C, these hemostatic bandages remain capable of releasing active nanofibers. In addition, the application of these nanofiber-based films from gauze bandages was found to accelerate hemostasis in porcine skin wounds as compared to plain gauze. The thermal robustness, in combination with the self-assembling peptide's potent hemostatic activity, biocompatibility, biodegradability, and low cost of production, makes this a promising approach for a cheap yet effective hemostatic bandage.
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Ferrogels are an attractive material for many biomedical applications due to their ability to deliver a wide variety of therapeutic drugs on-demand. However, typical ferrogels have yet to be optimized for use in cell-based therapies, as... more
Ferrogels are an attractive material for many biomedical applications due to their ability to deliver a wide variety of therapeutic drugs on-demand. However, typical ferrogels have yet to be optimized for use in cell-based therapies, as they possess limited ability to harbor and release viable cells. Previously, an active porous scaffold that exhibits large deformations and enhanced biological agent release under moderate magnetic fields has been demonstrated. Unfortunately, at small device sizes optimal for implantation (e.g., 2 mm thickness), these monophasic ferrogels no longer achieve significant deformation due to a reduced body force. A new biphasic ferrogel, containing an iron oxide gradient, capable of large deformations and triggered release even at small gel dimensions, is presented in this study. Biphasic ferrogels demonstrate increased porosity, enhanced mechanical properties, and potentially increased biocompatibility due to their reduced iron oxide content. With their ability to deliver drugs and cells on-demand, it is expected that these ferrogels will have wide utility in the fields of tissue engineering and regenerative medicine.
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Many strategies for controlling the fate of transplanted stem cells rely on the concurrent delivery of soluble growth factors that have the potential to produce undesirable secondary effects in surrounding tissue. Such off target effects... more
Many strategies for controlling the fate of transplanted stem cells rely on the concurrent delivery of soluble growth factors that have the potential to produce undesirable secondary effects in surrounding tissue. Such off target effects could be eliminated by locally presenting growth factor peptide mimics from biomaterial scaffolds to control stem cell fate. Peptide mimics of bone morphogenetic protein 2 (BMP-2) were synthesized by solid phase Fmoc-peptide synthesis and covalently bound to alginate hydrogels via either carbodiimide or sulfhydryl-based coupling strategies. Successful peptide conjugation was confirmed by (1)H NMR spectroscopy and quantified by fluorescently labeling the peptides. Peptides derived from the knuckle epitope of BMP-2, presented from both 2D surfaces and 3D alginate hydrogels, were shown to increase alkaline phosphatase activity in clonally derived murine osteoblasts. Furthermore, when presented in 3D hydrogels, these peptides were shown to initiate Smad signaling, upregulate osteopontin production, and increase mineral deposition with clonally derived murine mesenchymal stem cells. These data suggest that these peptide-conjugated hydrogels may be effective alternatives to local BMP-2 release in directly and spatially eliciting osteogenesis from transplanted or host osteoprogenitors in the future.
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Biomaterials may improve outcomes of endothelial progenitor-based therapies for the treatment of ischemic cardiovascular disease, due to their ability to direct cell behavior. We hypothesized that local, sustained delivery of exogenous... more
Biomaterials may improve outcomes of endothelial progenitor-based therapies for the treatment of ischemic cardiovascular disease, due to their ability to direct cell behavior. We hypothesized that local, sustained delivery of exogenous vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF) from alginate hydrogels could increase recruitment of systemically infused endothelial progenitors to ischemic tissue, and subsequent neovascularization. VEGF and SDF were found to enhance in vitro adhesion and migration of outgrowth endothelial cells (OECs) and circulating angiogenic cells (CACs), two populations of endothelial progenitors, by twofold to sixfold, and nearly doubled recruitment to both ischemic and nonischemic muscle tissue in vivo. Local delivery of VEGF and SDF to ischemic hind-limbs in combination with systemic CAC delivery significantly improved functional perfusion recovery over OEC delivery, or either treatment alone. Compared with OECs, CACs were more responsive to VEGF and SDF treatment, promoted in vitro endothelial sprout formation in a paracrine manner more potently, and demonstrated greater influence on infiltrating inflammatory cells in vivo. These studies demonstrate that accumulation of infused endothelial progenitors can be enriched using biomaterial-based delivery of VEGF and SDF, and emphasize the therapeutic benefit of using CACs for the treatment of ischemia.