Honors & Awards
The NIH Ruth L. Kirschstein National Research Service Award (NRSA) Postdoctoral Fellowship F32, National Institute of Health (2019)
Stanford Dean's Post-doctoral Fellowship, Stanford University (2018)
Alliance for Regenerative Rehabilitation Research and Training Travel Award, Symposium on Regenerative Rehabilitation, University of Pittsburgh (2017)
30 Under 30 in Healthcare, Forbes Magazine (2016)
Baxter Young Investigator Award, 1st Tier Highest Award Category, Baxter Healthcare (2016)
Foundation Capital Founder's Program Finalist, Foundation Capital, Foundation Capital (2015)
American Society for Artificial Internal Organs (ASAIO) Fellowship, American Society for Artificial Internal Organs (ASAIO) (2013)
Chancellor's Predoctoral Fellowship, University of California Berkeley (2011-2013)
National Science Foundation (NSF) Graduate Research Fellowship (GRFP), National Science Foundation (NSF) (2010-2016)
Doctor of Philosophy, University of California Berkeley (2016)
Doctor of Philosophy, University of California San Francisco (2016)
Bachelor of Science, Brown University, Biomedical Engineering
Paul George, Postdoctoral Faculty Sponsor
Electrical stimulation of human neural stem cells via conductive polymer nerve guides enhances peripheral nerve recovery.
2021; 275: 120982
Severe peripheral nerve injuries often result in permanent loss of function of the affected limb. Current treatments are limited by their efficacy in supporting nerve regeneration and behavioral recovery. Here we demonstrate that electrical stimulation through conductive nerve guides (CNGs) enhances the efficacy of human neural progenitor cells (hNPCs) in treating a sciatic nerve transection in rats. Electrical stimulation strengthened the therapeutic potential of NPCs by upregulating gene expression of neurotrophic factors which are critical in augmenting synaptic remodeling, nerve regeneration, and myelination. Electrically-stimulated hNPC-containing CNGs are significantly more effective in improving sensory and motor functions starting at 1-2 weeks after treatment than either treatment alone. Electrophysiology and muscle assessment demonstrated successful re-innervation of the affected target muscles in this group. Furthermore, histological analysis highlighted an increased number of regenerated nerve fibers with thicker myelination in electrically-stimulated hNPC-containing CNGs. The elevated expression of tyrosine kinase receptors (Trk) receptors, known to bind to neurotrophic factors, indicated the long-lasting effect from electrical stimulation on nerve regeneration and distal nerve re-innervation. These data suggest that electrically-enhanced stem cell-based therapy provides a regenerative rehabilitative approach to promote peripheral nerve regeneration and functional recovery.
View details for DOI 10.1016/j.biomaterials.2021.120982
View details for PubMedID 34214785
Morphing electronics enable neuromodulation in growing tissue.
Bioelectronics for modulating the nervous system have shown promise in treating neurological diseases1-3. However, their fixed dimensions cannot accommodate rapid tissue growth4,5 and may impair development6. For infants, children and adolescents, once implanted devices are outgrown, additional surgeries are often needed for device replacement, leading to repeated interventions and complications6-8. Here, we address this limitation with morphing electronics, which adapt to in vivo nerve tissue growth with minimal mechanical constraint. We design and fabricate multilayered morphing electronics, consisting of viscoplastic electrodes and a strain sensor that eliminate the stress at the interface between the electronics and growing tissue. The ability of morphing electronics to self-heal during implantation surgery allows a reconfigurable and seamless neural interface. During the fastest growth period in rats, morphing electronics caused minimal damage to the rat nerve, which grows 2.4-fold in diameter, and allowed chronic electrical stimulation and monitoring for 2 months without disruption of functional behavior. Morphing electronics offers a path toward growth-adaptive pediatric electronic medicine.
View details for DOI 10.1038/s41587-020-0495-2
View details for PubMedID 32313193
Controlling properties of human neural progenitor cells using 2D and 3D conductive polymer scaffolds.
2019; 9 (1): 19565
Human induced pluripotent stem cell-derived neural progenitor cells (hNPCs) are a promising cell source for stem cell transplantation to treat neurological diseases such as stroke and peripheral nerve injuries. However, there have been limited studies investigating how the dimensionality of the physical and electrical microenvironment affects hNPC function. In this study, we report the fabrication of two- and three-dimensional (2D and 3D respectively) constructs composed of a conductive polymer to compare the effect of electrical stimulation of hydrogel-immobilized hNPCs. The physical dimension (2D vs 3D) of stimulating platforms alone changed the hNPCs gene expression related to cell proliferation and metabolic pathways. The addition of electrical stimulation was critical in upregulating gene expression of neurotrophic factors that are important in regulating cell survival, synaptic remodeling, and nerve regeneration. This study demonstrates that the applied electrical field controls hNPC properties depending on the physical nature of stimulating platforms and cellular metabolic states. The ability to control hNPC functions can be beneficial in understanding mechanistic changes related to electrical modulation and devising novel treatment methods for neurological diseases.
View details for DOI 10.1038/s41598-019-56021-w
View details for PubMedID 31863072
An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport.
Lab on a chip
2017; 17 (10): 1778–92
Diffusion-based bioartificial pancreas (BAP) devices are limited by poor islet viability and functionality due to inadequate mass transfer resulting in islet hypoxia and delayed glucose-insulin kinetics. While intravascular ultrafiltration-based BAP devices possess enhanced glucose-insulin kinetics, the polymer membranes used in these devices provide inadequate ultrafiltrate flow rates and result in excessive thrombosis. Here, we report the silicon nanopore membrane (SNM), which exhibits a greater hydraulic permeability and a superior pore size selectivity compared to polymer membranes for use in BAP applications. Specifically, we demonstrate that the SNM-based intravascular BAP with ∼10 and ∼40 nm pore sized membranes support high islet viability (>60%) and functionality (<15 minute insulin response to glucose stimulation) at clinically relevant islet densities (5700 and 11 400 IE per cm2) under convection in vitro. In vivo studies with ∼10 nm pore sized SNM in a porcine model showed high islet viability (>85%) at clinically relevant islet density (5700 IE per cm2), c-peptide concentration of 144 pM in the outflow ultrafiltrate, and hemocompatibility under convection. These promising findings offer insights on the development of next generation of full-scale intravascular devices to treat T1D patients in the future.
View details for DOI 10.1039/c7lc00096k
View details for PubMedID 28426078
View details for PubMedCentralID PMC5573191
Glucose-Stimulated Insulin Response of Silicon Nanopore-Immunoprotected Islets under Convective Transport.
ACS biomaterials science & engineering
2017; 3 (6): 1051–61
Major clinical challenges associated with islet transplantation for type 1 diabetes include shortage of donor organs, poor engraftment due to ischemia, and need for immunosuppressive medications. Semipermeable membrane capsules can immunoprotect transplanted islets by blocking passage of the host's immune components while providing exchange of glucose, insulin, and other small molecules. However, capsules-based diffusive transport often exacerbates ischemic injury to islets by reducing the rate of oxygen and nutrient transport. We previously reported the efficacy of a newly developed semipermeable ultrafiltration membrane, the silicon nanopore membrane (SNM) under convective-driven transport, in limiting the passage of pro-inflammatory cytokines while overcoming the mass transfer limitations associated with diffusion through nanometer-scale pores. In this study, we report that SNM-encapsulated mouse islets perfused in culture solution under convection outperformed those under diffusive conditions in terms of magnitude (1.49-fold increase in stimulation index and 3.86-fold decrease in shutdown index) and rate of insulin secretion (1.19-fold increase and 6.45-fold decrease during high and low glucose challenges), respectively. Moreover, SNM-encapsulated mouse islets under convection demonstrated rapid glucose-insulin sensing within a physiologically relevant time-scale while retaining healthy islet viability even under cytokine exposure. We conclude that encapsulation of islets with SNM under convection improves islet in vitro functionality. This approach may provide a novel strategy for islet transplantation in the clinical setting.
View details for DOI 10.1021/acsbiomaterials.6b00814
View details for PubMedID 29250596
View details for PubMedCentralID PMC5729757
Silicon nanopore membrane (SNM) for islet encapsulation and immunoisolation under convective transport
Problems associated with islet transplantation for Type 1 Diabetes (T1D) such as shortage of donor cells, use of immunosuppressive drugs remain as major challenges. Immune isolation using encapsulation may circumvent the use of immunosuppressants and prolong the longevity of transplanted islets. The encapsulating membrane must block the passage of host's immune components while providing sufficient exchange of glucose, insulin and other small molecules. We report the development and characterization of a new generation of semipermeable ultrafiltration membrane, the silicon nanopore membrane (SNM), designed with approximately 7 nm-wide slit-pores to provide middle molecule selectivity by limiting passage of pro-inflammatory cytokines. Moreover, the use of convective transport with a pressure differential across the SNM overcomes the mass transfer limitations associated with diffusion through nanometer-scale pores. The SNM exhibited a hydraulic permeability of 130 ml/hr/m(2)/mmHg, which is more than 3 fold greater than existing polymer membranes. Analysis of sieving coefficients revealed 80% reduction in cytokines passage through SNM under convective transport. SNM protected encapsulated islets from infiltrating cytokines and retained islet viability over 6 hours and remained responsive to changes in glucose levels unlike non-encapsulated controls. Together, these data demonstrate the novel membrane exhibiting unprecedented hydraulic permeability and immune-protection for islet transplantation therapy.
View details for DOI 10.1038/srep23679
View details for PubMedCentralID PMC4806308
Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: Cells, biomaterials, and devices.
Biotechnology and bioengineering
2016; 113 (7): 1381–1402
Macroencapsulation technology has been an attractive topic in the field of treatment for Type 1 diabetes due to mechanical stability, versatility, and retrievability of the macro-capsule design. Macro-capsules can be categorized into extravascular and intravascular devices, in which solute transport relies either on diffusion or convection, respectively. Failure of macroencapsulation strategies can be due to limited regenerative capacity of the encased insulin-producing cells, sub-optimal performance of encapsulation biomaterials, insufficient immunoisolation, excessive blood thrombosis for vascular perfusion devices, and inadequate modes of mass transfer to support cell viability and function. However, significant technical advancements have been achieved in macroencapsulation technology, namely reducing diffusion distance for oxygen and nutrients, using pro-angiogenic factors to increase vascularization for islet engraftment, and optimizing membrane permeability and selectivity to prevent immune attacks from host's body. This review presents an overview of existing macroencapsulation devices and discusses the advances based on tissue-engineering approaches that will stimulate future research and development of macroencapsulation technology. Biotechnol. Bioeng. 2016;113: 1381-1402. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/bit.25895
View details for PubMedID 26615050
View details for PubMedCentralID PMC5873326
The synergistic effect of micro-topography and biochemical culture environment to promote angiogenesis and osteogenic differentiation of human mesenchymal stem cells.
2015; 18: 100–111
Critical failures associated with current engineered bone grafts involve insufficient induction of osteogenesis of the implanted cells and lack of vascular integration between graft scaffold and host tissue. This study investigated the combined effects of surface microtextures and biochemical supplements to achieve osteogenic differentiation of human mesenchymal stem cells (hMSCs) and revascularization of the implants in vivo. Cells were cultured on 10μm micropost-textured polydimethylsiloxane (PDMS) substrates in either proliferative basal medium (BM) or osteogenic medium (OM). In vitro data revealed that cells on microtextured substrates in OM had dense coverage of extracellular matrix, whereas cells in BM displayed more cell spreading and branching. Cells on microtextured substrates in OM demonstrated a higher gene expression of osteoblast-specific markers, namely collagen I, alkaline phosphatase, bone sialoprotein, and osteocalcin, accompanied by substantial amount of bone matrix formation and mineralization. To further investigate the osteogenic capacity, hMSCs on microtextured substrates under different biochemical stimuli were implanted into subcutaneous pockets on the dorsal aspect of immunocompromised mice to study capacity for ectopic bone formation. In vivo data revealed greater expression of osteoblast-specific markers coupled with increased vascular invasion on microtextured substrates with hMSCs cultured in OM. Together, these data represent a novel regenerative strategy that incorporates defined surface microtextures and biochemical stimuli to direct combined osteogenesis and re-vascularization of engineered bone scaffolds for musculoskeletal repair and relevant bone tissue engineering applications.
View details for DOI 10.1016/j.actbio.2015.02.021
View details for PubMedID 25735800
Elastin-like Proteins to Support Peripheral Nerve Regeneration in Guidance Conduits.
ACS biomaterials science & engineering
2021; 7 (9): 4209-4220
Synthetic nerve guidance conduits (NGCs) offer an alternative to harvested nerve grafts for treating peripheral nerve injury (PNI). NGCs have been made from both naturally derived and synthesized materials. While naturally derived materials typically have an increased capacity for bioactivity, synthesized materials have better material control, including tunability and reproducibility. Protein engineering is an alternative strategy that can bridge the benefits of these two classes of materials by designing cell-responsive materials that are also systematically tunable and consistent. Here, we tested a recombinantly derived elastin-like protein (ELP) hydrogel as an intraluminal filler in a rat sciatic nerve injury model. We demonstrated that ELPs enhance the probability of forming a tissue bridge between the proximal and distal nerve stumps compared to an empty silicone conduit across the length of a 10 mm nerve gap. These tissue bridges have evidence of myelinated axons, and electrophysiology demonstrated that regenerated axons innervated distal muscle groups. Animals implanted with an ELP-filled conduit had statistically higher functional control at 6 weeks than those that had received an empty silicone conduit, as evaluated by the sciatic functional index. Taken together, our data support the conclusion that ELPs support peripheral nerve regeneration in acute complete transection injuries when used as an intraluminal filler. These results support the further study of protein engineered recombinant ELP hydrogels as a reproducible, off-the-shelf alternative for regeneration of peripheral nerves.
View details for DOI 10.1021/acsbiomaterials.0c01053
View details for PubMedID 34510904
Regulating Stem Cell Function with Electrical Stimulation
WILEY. 2019: S277–S278
View details for Web of Science ID 000488891800447
In vivo Electrical Stimulation of Neural Stem Cells via Conductive Polymer Scaffold Improves Endogenous Repair Mechanisms of Stroke Recovery
LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000453090802415
- Electrically Conductive Scaffold to Modulate and Deliver Stem Cells JOVE-JOURNAL OF VISUALIZED EXPERIMENTS 2018
Electrically Conductive Scaffold to Modulate and Deliver Stem Cells.
Journal of visualized experiments : JoVE
Stem cell therapy has emerged as an exciting stroke therapeutic, but the optimal delivery method remains unclear. While the technique of microinjection has been used for decades to deliver stem cells in stroke models, this technique is limited by the lack of ability to manipulate the stem cells prior to injection. This paper details a method of using an electrically conductive polymer scaffold for stem cell delivery. Electrical stimulation of stem cells using a conductive polymer scaffold alters the stem cell's genes involved in cell survival, inflammatory response, and synaptic remodeling. After electrical preconditioning, the stem cells on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. This protocol describes a powerful technique to manipulate stem cells via a conductive polymer scaffold and creates a new tool to further develop stem cell-based therapy.
View details for PubMedID 29708538
- Conductive polymer scaffolds to improve neural recovery. Neural regeneration research 2017; 12 (12): 1976–78
- Self-assembled rosette nanotubes encapsulate and slowly release dexamethasone Int J Nanomedicine 2011
- Self-assembled Rosette Nanotubes (RNTs) for Incorporating Hydrophobic Drug in Physiological Environment Int J Nanomedicine 2011
- Controlled Release of Tetracycline-HCL from Halloysite-Polymer Composite Films J Nanosci Nanotechnol 2010