A wireless, implantable bioelectronic system for monitoring urinary bladder function following surgical recovery.

Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients. Here, we introduce a fully bladder-implantable platform that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. We demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 d postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 wk compared with traditional UDS. These results suggest that our system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring.

Potent laminin-inspired antioxidant regenerative dressing accelerates wound healing in diabetes.

The successful treatment of chronic dermal wounds, such as diabetic foot ulcers (DFU), depends on the development of safe, effective, and affordable regenerative tools that the surgeon can rely on to promote wound closure. Although promising, strategies that involve cell-based therapies and the local release of exogenous growth factors are costly, require very long development times, and result in modest improvements in patient outcome. We describe the development of an antioxidant shape-conforming regenerative wound dressing that uses the laminin-derived dodecapeptide A5G81 as a potent tethered cell adhesion-, proliferation-, and haptokinesis-inducing ligand to locally promote wound closure. A5G81 immobilized within a thermoresponsive citrate-based hydrogel facilitates integrin-mediated spreading, migration, and proliferation of dermal and epidermal cells, resulting in faster tissue regeneration in diabetic wounds. This peptide-hydrogel system represents a paradigm shift in dermoconductive and dermoinductive strategies for treating DFU without the need for soluble biological or pharmacological factors.

Cyclodextrin-modified poly(octamethylene citrate) polymers towards enhanced sorption properties.

Herein, we describe the synthesis of poly(1,8-octamethylene citrate) materials modified in the bulk with 2-hydroxypropyl-ß-cyclodextrin (cPOCCD), biodegradable elastomers with intrinsic sorption properties for drug delivery. The chemical structure, physicochemical properties, in vitro drug loading and release profiles of cPOCCD were investigated. Thus, cPOCCD polyesters absorb the studied drugs more effective and release them for a longer period of time than poly(1,8-octamethylene citrate) materials not containing cyclodextrins.

Bone Morphogenetic Protein-9-Stimulated Adipocyte-Derived Mesenchymal Progenitors Entrapped in a Thermoresponsive Nanocomposite Scaffold Facilitate Cranial Defect Repair.

Due to availability and ease of harvest, adipose tissue is a favorable source of progenitor cells in regenerative medicine, but has yet to be optimized for osteogenic differentiation. The purpose of this study was to test cranial bone healing in a surgical defect model utilizing bone morphogenetic protein-9 (BMP-9) transduced immortalized murine adipocyte (iMAD) progenitor cells in a citrate-based, phase-changing, poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN)-gelatin scaffold. Mesenchymal progenitor iMAD cells were transduced with adenovirus expressing either BMP-9 or green fluorescent protein control. Twelve mice underwent craniectomy to achieve a critical-sized cranial defect. The iMAD cells were mixed with the PPCN-gelatin scaffold and injected into the defects. MicroCT imaging was performed in 2-week intervals for 12 weeks to track defect healing. Histologic analysis was performed on skull sections harvested after the final imaging at 12 weeks to assess quality and maturity of newly formed bone. Both the BMP-9 group and control group had similar initial defect sizes (P = 0.21). At each time point, the BMP-9 group demonstrated smaller defect size, higher percentage defect healed, and larger percentage defect change over time. At the end of the 12-week period, the BMP-9 group demonstrated mean defect closure of 27.39%, while the control group showed only a 9.89% defect closure (P < 0.05). The BMP-9-transduced iMADs combined with a PPCN-gelatin scaffold promote in vivo osteogenesis and exhibited significantly greater osteogenesis compared to control. Adipose-derived iMADs are a promising source of mesenchymal stem cells for further studies in regenerative medicine, specifically bone engineering with the aim of potential craniofacial applications.

Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs).

BACKGROUND/AIMS: Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into several lineages including bone. Successful bone formation requires osteogenesis and angiogenesis coupling of MSCs. Here, we investigate if simultaneous activation of BMP9 and Notch signaling yields effective osteogenesis-angiogenesis coupling in MSCs. METHODS: Recently-characterized immortalized mouse adipose-derived progenitors (iMADs) were used as MSC source. Transgenes BMP9, NICD and dnNotch1 were expressed by adenoviral vectors. Gene expression was determined by qPCR and immunohistochem¡stry. Osteogenic activity was assessed by in vitro assays and in vivo ectopic bone formation model. RESULTS: BMP9 upregulated expression of Notch receptors and ligands in iMADs. Constitutively-active form of Notch1 NICD1 enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo, which was effectively inhibited by dominant-negative form of Notch1 dnNotch1. BMP9- and NICD1-transduced MSCs implanted with a biocompatible scaffold yielded highly mature bone with extensive vascularization. NICD1 enhanced BMP9-induced expression of key angiogenic regulators in iMADs and Vegfa in ectopic bone, which was blunted by dnNotch1. CONCLUSION: Notch signaling may play an important role in BMP9-induced osteogenesis and angiogenesis. It's conceivable that simultaneous activation of the BMP9 and Notch pathways should efficiently couple osteogenesis and angiogenesis of MSCs for successful bone tissue engineering.

A Cooperative Copper Metal-Organic Framework-Hydrogel System Improves Wound Healing in Diabetes.

Chronic non-healing wounds remain a major clinical challenge that would benefit from the development of advanced, regenerative dressings that promote wound closure within a clinically relevant time frame. The use of copper ions has shown promise in wound healing applications possibly by promoting angiogenesis. However, reported treatments that use copper ions require multiple applications of copper salts or oxides to the wound bed, exposing the patient to potentially toxic levels of copper ions and resulting in variable outcomes. Herein we set out to assess whether copper metal organic framework nanoparticles (HKUST-1 NPs) embedded within an antioxidant thermoresponsive citrate-based hydrogel would decrease copper ion toxicity and accelerate wound healing in diabetic mice. HKUST-1 and poly-(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) were synthesized and characterized. HKUST-1 NP stability in a protein solution with and without embedding them in PPCN hydrogel was determined. Copper ion release, cytotoxicity, apoptosis, and in vitro migration processes were measured. Wound closure rates and wound blood perfusion were assessed in vivo using the splinted excisional dermal wound diabetic mouse model. HKUST-1 NP disintegrated in protein solution while HKUST-1 NPs embedded in PPCN (H-HKUST-1) were protected from degradation and copper ions were slowly released. Cytotoxicity and apoptosis due to copper ion release were significantly reduced while dermal cell migration in vitro and wound closure rates in vivo were significantly enhanced. In vivo, H-HKUST-1 induced angiogenesis, collagen deposition, and re-epithelialization during wound healing in diabetic mice. These results suggest that a cooperatively stabilized, copper ion-releasing H-HKUST-1 hydrogel is a promising innovative dressing for the treatment of chronic wounds.

Assessment of an engineered endothelium via single-photon emission computed tomography.

The clinical translation of cell-based therapeutics often requires highly sensitive, non-invasive imaging tools to assess cell function and distribution in vivo. The objective of this research was to determine whether human Sodium-Iodide Symporter (hNIS) ectopic expression in endothelial cells (ECs) in combination with single-photon emission computed tomography (SPECT) is a feasible approach to non-invasively monitor the presence and viability of an engineered endothelium on expanded polytetrafluoroethylene (ePTFE). Human umbilical vein endothelial cells (HUVECs) were transduced with pLL3.7-hNIS via lentivirus with multiplicity of infection (MOI) of 0, 2, 5, and 10 (n = 4). Ectopic expression of hNIS in HUVECs via optimized lentiviral transduction (MOI 5) enabled cell uptake of a radioisotope that can be detected by SPECT without affecting endothelial cell viability, oxidative stress, or antithrombogenic functions. The viability and distribution of an engineered endothelium grown on ePTFE coated with the biodegradable elastomer poly(1, 8 octamethylene citrate) (POC) and exposed to fluid flow was successfully monitored non-invasively by SPECT. We report the feasibility of a non-invasive, highly sensitive and functional assessment of an engineered endothelium on ePTFE using a combination of SPECT and X-ray computed tomography (SPECT/CT) imaging and hNIS ectopic expression in ECs. This technology potentially allows for the non-invasive assessment of transplanted living cells in vascular conduits. Biotechnol. Bioeng. 2017;114: 2371-2377. © 2017 Wiley Periodicals, Inc.

Structural behavior of competitive temperature and pH-responsive tethered polymer layers.

Herein, we develop a molecular theory to examine a class of pH and temperature-responsive tethered polymer layers. The response of pH depends on intramolecular charge repulsion of weakly acidic monomers and the response of temperature depends on hydrogen bonding between polymer monomers and water molecules akin to the behavior of water-soluble polymers such as PEG (poly-ethylene glycol) or NIPAAm (n-isopropylacrylamide). We investigate the changes in structural behavior that result for various end-tethered copolymers: pH/T responsive monomers alone, in alternating sequence with hydrophobic monomers, and as 50/50 diblocks with hydrophobic monomers. We find that the sequence and location of hydrophobic units play a critical role in the thermodynamic stability and structural behavior of these responsive polymer layers. Additionally, the polymers exhibit tunable collapse when varying the surface coverage, location and sequence of hydrophobic units as a function of temperature and pH. As far as we know, our results present the first molecularly detailed theory for end-tethered polymers that are both pH and temperature-responsive via hydrogen bonding. We propose that this work holds predictive power for the guided design of future biomaterials.

Targeting Heparin to Collagen within Extracellular Matrix Significantly Reduces Thrombogenicity and Improves Endothelialization of Decellularized Tissues.

Thrombosis within small-diameter vascular grafts limits the development of bioartificial, engineered vascular conduits, especially those derived from extracellular matrix (ECM). Here we describe an easy-to-implement strategy to chemically modify vascular ECM by covalently linking a collagen binding peptide (CBP) to heparin to form a heparin derivative (CBP-heparin) that selectively binds a subset of collagens. Modification of ECM with CBP-heparin leads to increased deposition of functional heparin (by ∼7.2-fold measured by glycosaminoglycan composition) and a corresponding reduction in platelet binding (>70%) and whole blood clotting (>80%) onto the ECM. Furthermore, addition of CBP-heparin to the ECM stabilizes long-term endothelial cell attachment to the lumen of ECM-derived vascular conduits, potentially through recruitment of heparin-binding growth factors that ultimately improve the durability of endothelialization in vitro. Overall, our findings provide a simple yet effective method to increase deposition of functional heparin on the surface of ECM-based vascular grafts and thereby minimize thrombogenicity of decellularized tissue, overcoming a significant challenge in tissue engineering of bioartificial vessels and vascularized organs.

Cotransplantation with specific populations of spina bifida bone marrow stem/progenitor cells enhances urinary bladder regeneration.

Spina bifida (SB) patients afflicted with myelomeningocele typically possess a neurogenic urinary bladder and exhibit varying degrees of bladder dysfunction. Although surgical intervention in the form of enterocystoplasty is the current standard of care in which to remedy the neurogenic bladder, it is still a stop-gap measure and is associated with many complications due to the use of bowel as a source of replacement tissue. Contemporary bladder tissue engineering strategies lack the ability to reform bladder smooth muscle, vasculature, and promote peripheral nerve tissue growth when using autologous populations of cells. Within the context of this study, we demonstrate the role of two specific populations of bone marrow (BM) stem/progenitor cells used in combination with a synthetic elastomeric scaffold that provides a unique and alternative means to current bladder regeneration approaches. In vitro differentiation, gene expression, and proliferation are similar among donor mesenchymal stem cells (MSCs), whereas poly(1,8-octanediol-cocitrate) scaffolds seeded with SB BM MSCs perform analogously to control counterparts with regard to bladder smooth muscle wall formation in vivo. SB CD34(+) hematopoietic stem/progenitor cells cotransplanted with donor-matched MSCs cause a dramatic increase in tissue vascularization as well as an induction of peripheral nerve growth in grafted areas compared with samples not seeded with hematopoietic stem/progenitor cells. Finally, MSC/CD34(+) grafts provided the impetus for rapid urothelium regeneration. Data suggest that autologous BM stem/progenitor cells may be used as alternate, nonpathogenic cell sources for SB patient-specific bladder tissue regeneration in lieu of current enterocystoplasty procedures and have implications for other bladder regenerative therapies.

Biodegradable elastomers and silicon nanomembranes/nanoribbons for stretchable, transient electronics, and biosensors.

Transient electronics represents an emerging class of technology that exploits materials and/or device constructs that are capable of physically disappearing or disintegrating in a controlled manner at programmed rates or times. Inorganic semiconductor nanomaterials such as silicon nanomembranes/nanoribbons provide attractive choices for active elements in transistors, diodes and other essential components of overall systems that dissolve completely by hydrolysis in biofluids or groundwater. We describe here materials, mechanics, and design layouts to achieve this type of technology in stretchable configurations with biodegradable elastomers for substrate/encapsulation layers. Experimental and theoretical results illuminate the mechanical properties under large strain deformation. Circuit characterization of complementary metal-oxide-semiconductor inverters and individual transistors under various levels of applied loads validates the design strategies. Examples of biosensors demonstrate possibilities for stretchable, transient devices in biomedical applications.

Periadventitial atRA citrate-based polyester membranes reduce neointimal hyperplasia and restenosis after carotid injury in rats.

Oral all-trans retinoic acid (atRA) has been shown to reduce the formation of neointimal hyperplasia; however, the dose required was 30 times the chemotherapeutic dose, which already has reported side effects. As neointimal formation is a localized process, new approaches to localized delivery are required. This study assessed whether atRA within a citrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimal hyperplasia following arterial injury. atRA-POC membranes were prepared and characterized for atRA release via high-performance liquid chromatography with mass spectrometry detection. Rat adventitial fibroblasts (AF) and vascular smooth muscle cells (VSMC) were exposed to various concentrations of atRA; proliferation, apoptosis, and necrosis were assessed in vitro. The rat carotid artery balloon injury model was used to evaluate the impact of the atRA-POC membranes on neointimal formation, cell proliferation, apoptosis, macrophage infiltration, and vascular cell adhesion molecule 1 (VCAM-1) expression in vivo. atRA-POC membranes released 12 µg of atRA over 2 wk, with 92% of the release occurring in the first week. At 24 h, atRA (200 µmol/l) inhibited [(3)H]-thymidine incorporation into AF and VSMC by 78% and 72%, respectively (*P = 0.001), with negligible apoptosis or necrosis. Histomorphometry analysis showed that atRA-POC membranes inhibited neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, intima-to-media area ratio, and percent stenosis, respectively (P = 0.001). atRA-POC membranes had no appreciable effect on apoptosis or proliferation at 2 wk. Regarding biocompatibility, we found a 76% decrease in macrophage infiltration in the intima layer (P < 0.003) in animals treated with atRA-POC membranes, with a coinciding 53% reduction in VCAM-1 staining (P < 0.001). In conclusion, perivascular delivery of atRA inhibited neointimal formation and restenosis. These data suggest that atRA-POC membranes may be suitable as localized therapy to inhibit neointimal hyperplasia following open cardiovascular procedures.

Albumin hydrogels formed by electrostatically triggered self-assembly and their drug delivery capability.

Biological hydrogels are fundamentally biocompatible and have intrinsic similarities to extracellular matrices in medical applications and drug delivery systems. Herein we demonstrate the ability to form drug-eluting protein hydrogels using a novel mechanism that involves the electrostatically triggered partial denaturation and self-assembly of the protein via changes in pH. Partial denaturation increases the protein's solvent exposed hydrophobic surface area, which then drives self-assembly of the protein into a hydrogel within 10 min at 37 °C. We describe the properties of an albumin hydrogel formed by this mechanism. Intrinsic drug binding properties of albumin to all-trans retinoic acid (atRA) are conserved through the partial denaturation process, as confirmed by fluorescence quenching. atRA released from the hydrogel inhibited smooth muscle cell migration as per an in vitro scratch wound assay. Atomistic molecular dynamics and potential of mean force calculations show the preservation and potential creation of new atRA binding sites with a binding energy of -41 kJ/mol. The resulting hydrogel is also biocompatible and exhibits rapid postgelation degradation after its implantation in vivo. This interdisciplinary work provides a new tool for the development of biocompatible protein hydrogel drug delivery systems.

A thermoresponsive biodegradable polymer with intrinsic antioxidant properties.

Oxidative stress in tissue can contribute to chronic inflammation that impairs wound healing and the efficacy of cell-based therapies and medical devices. We describe the synthesis and characterization of a biodegradable, thermoresponsive gel with intrinsic antioxidant properties suitable for the delivery of therapeutics. Citric acid, poly(ethylene glycol) (PEG), and poly-N-isopropylacrylamide (PNIPAAm) were copolymerized by sequential polycondensation and radical polymerization to produce poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN). PPCN was chemically characterized, and the thermoresponsive behavior, antioxidant properties, morphology, potential for protein and cell delivery, and tissue compatibility in vivo were evaluated. The PPCN gel has a lower critical solution temperature (LCST) of 26 °C and exhibits intrinsic antioxidant properties based on its ability to scavenge free radicals, chelate metal ions, and inhibit lipid peroxidation. PPCN displays a hierarchical architecture of micropores and nanofibers, and contrary to typical thermoresponsive polymers, such as PNIPAAm, PPCN gel maintains its volume upon formation. PPCN efficiently entrapped and slowly released the chemokine SDF-1α and supported the viability and proliferation of vascular cells. Subcutaneous injections in rats showed that PPCN gels are resorbed over time and new connective tissue formation takes place without signs of significant inflammation. Ultimately, this intrinsically antioxidant, biodegradable, thermoresponsive gel could potentially be used as an injectable biomaterial for applications where oxidative stress in tissue is a concern.

A receptor-based bioadsorbent to target advanced glycation end products in chronic kidney disease.

The accumulation of advanced glycation end products (AGEs) has been reported to be a major contributor to chronic systemic inflammation. AGEs are not efficiently removed by hemodialysis or the kidney of a chronic kidney disease (CKD) patient. The goal of this study was to develop a receptor for AGEs (RAGE)-based bioadsorbent device that was capable of removing endogenous AGEs from human blood. The extracellular domain of RAGE was immobilized onto agarose beads to generate the bioadsorbent. The efficacy of AGE removal from saline, serum, and whole blood; biological effects of AGE reduction; and hemocompatibility and stability of the bioadsorbent were investigated. The bioadsorbent bound AGE-modified bovine serum albumin (AGE-BSA) with a binding capacity of 0.73 ± 0.07 mg AGE-BSA/mL bioadsorbent. The bioadsorbent significantly reduced the concentration of total AGEs in serum isolated from end-stage kidney disease patients by 57%. AGE removal resulted in a significant reduction of vascular cell adhesion molecule-1 expression in human endothelial cells and abolishment of osteoclast formation in osteoclast progenitor cells. A hollow fiber device loaded with bioadsorbent-reduced endogenous AGEs from recirculated blood to 36% of baseline levels with no significant changes in total protein or albumin concentration. The bioadsorbent maintained AGE-specific binding capacity after freeze-drying and storage for 1 year. This approach provides the foundation for further development of soluble RAGE-based extracorporeal therapies to selectively deplete serum AGEs from human blood and decrease inflammation in patients with diabetes and/or CKD.

Enabling Proregenerative Medical Devices via Citrate-Based Biomaterials: Transitioning from Inert to Regenerative Biomaterials.

Regenerative medicine aims to restore tissue and organ function without the use of prosthetics and permanent implants. However, achieving this goal has been elusive, and the field remains mostly an academic discipline with few products widely used in clinical practice. From a materials science perspective, barriers include the lack of proregenerative biomaterials, a complex regulatory process to demonstrate safety and efficacy, and user adoption challenges. Although biomaterials, particularly biodegradable polymers, can play a major role in regenerative medicine, their suboptimal mechanical and degradation properties often limit their use, and they do not support inherent biological processes that facilitate tissue regeneration. As of 2020, nine synthetic biodegradable polymers used in medical devices are cleared or approved for use in the United States of America. Despite the limitations in the design, production, and marketing of these devices, this small number of biodegradable polymers has dominated the resorbable medical device market for the past 50 years. This perspective will review the history and applications of biodegradable polymers used in medical devices, highlight the need and requirements for regenerative biomaterials, and discuss the path behind the recent successful introduction of citrate-based biomaterials for manufacturing innovative medical products aimed at improving the outcome of musculoskeletal surgeries.

Enabling Non-invasive Tracking of Vascular Endothelial Cells Derived from Induced Pluripotent Stem Cells Using Nuclear Imaging.

PURPOSE: The absence of clinically applicable imaging techniques for continuous monitoring of transplanted cells poses a significant obstacle to the clinical translation of stem cell-based therapies for vascular regeneration. This study aims to optimize a clinically applicable, non-invasive imaging technique to longitudinally monitor vascular endothelial cells (ECs) for vascular regeneration in peripheral artery disease (PAD). METHODS: Human induced pluripotent stem cells (HiPSCs) were employed to generate ECs (HiPSC-ECs). Lentiviral vectors encoding human sodium iodide symporter (hNIS) and enhanced green fluorescent protein (eGFP) genes were introduced to HiPSCs and HiPSC-ECs at varying multiplicities of infection (MOI). Through a combination of fluorescence microscopy and flow cytometry, an optimized transduction technique for introducing hNIS-eGFP into HiPSC-ECs was established. Subsequently, single-photon emission computed tomography (SPECT) was utilized for imaging of the transduced cells in vitro and in vivo after transplantation into the gastrocnemius muscle of nude mice. RESULTS: Lentiviral transduction resulted in sustained co-expression of hNIS and eGFP in HiPSC-ECs when transduced post-endothelial differentiation. An optimal MOI of five yielded over 90% hNIS-eGFP expression efficiency without compromising cell viability. hNIS-eGFP+ HiPSC-ECs exhibited 99mTc uptake and were detectable through SPECT in vitro. Additionally, intramuscular injection of hNIS-eGFP+ HiPSC-ECs with MatrigelTM into the hindlimbs of nude mice enabled real-time SPECT/CT tracking, from which a reduction in signal exceeding 80% was observed within 7 days. CONCLUSIONS: This study establishes an optimized cell modification and imaging protocol for tracking transplanted cells. Future efforts will focus on enhancing cell survival and integration via improved delivery systems, thereby advancing the potential of cell-based therapies for PAD.

Decoupling the Influence of Poly(3,4-Ethylenedioxythiophene)-Collagen Composite Characteristics on Cell Stemness.

Conductive polymers (CPs) are widely studied for their ability to influence a myriad of tissue systems. While their mixed ionic/electronic conductivity is commonly considered the primary driver of these benefits, the mechanisms by which CPs influence cell fate remain unclear. In this study, CP-biomaterial interactions are investigated using collagen, due to its widespread prevalence throughout the body and in tissue engineering constructs. Collagen is functionalized with both electrostatically and covalently bound derivatives of the CP poly(3,4-ethylenedioxythiophene) (PEDOT) doped via backbone-tethered sulfonate groups, which enable high solubility and loading to the collagen biomatrix. Intrinsically doped scaffolds are compared to those incorporated with a commercially available PEDOT formulation, which is complexed with polyanionic polystyrene sulfonate (PSS). Low loadings of intrinsically doped PEDOT do not increase substrate conductivity compared to collagen alone, enabling separate investigation into CP loading and conductivity. Interestingly, higher PEDOT loading bolsters human mesenchymal stromal (hMSC) cell gene expression of Oct-4 and NANOG, which are key transcription factors regulating cell stemness. Conductive collagen composites with commercial PEDOT:PSS do not significantly affect the expression of these transcription factors in hMSCs. Furthermore, it is demonstrated that PEDOT regulates cellular fate independently from physical changes to the material but directly to the loading of the polymer.

Cell-free biodegradable electroactive scaffold for urinary bladder regeneration.

Tissue engineering heavily relies on cell-seeded scaffolds to support the complex biological and mechanical requirements of a target organ. However, in addition to safety and efficacy, translation of tissue engineering technology will depend on manufacturability, affordability, and ease of adoption. Therefore, there is a need to develop scalable biomaterial scaffolds with sufficient bioactivity to eliminate the need for exogenous cell seeding. Herein, we describe synthesis, characterization, and implementation of an electroactive biodegradable elastomer for urinary bladder tissue engineering. To create an electrically conductive and mechanically robust scaffold to support bladder tissue regeneration, we developed a phase-compatible functionalization method wherein the hydrophobic conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) was polymerized in situ within a similarly hydrophobic citrate-based elastomer poly(octamethylene-citrate-co-octanol) (POCO) film. We demonstrate the efficacy of this film as a scaffold for bladder augmentation in athymic rats, comparing PEDOT-POCO scaffolds to mesenchymal stromal cell-seeded POCO scaffolds. PEDOT-POCO recovered bladder function and anatomical structure comparably to the cell-seeded POCO scaffolds and significantly better than non-cell seeded POCO scaffolds. This manuscript reports: (1) a new phase-compatible functionalization method that confers electroactivity to a biodegradable elastic scaffold, and (2) the successful restoration of the anatomy and function of an organ using a cell-free electroactive scaffold.

Citric Acid: A Nexus Between Cellular Mechanisms and Biomaterial Innovations.

Citrate-based biodegradable polymers have emerged as a distinctive biomaterial platform with tremendous potential for diverse medical applications. By harnessing their versatile chemistry, these polymers exhibit a wide range of material and bioactive properties, enabling them to regulate cell metabolism and stem cell differentiation through energy metabolism, metabonegenesis, angiogenesis, and immunomodulation. Moreover, the recent US Food and Drug Administration (FDA) clearance of the biodegradable poly(octamethylene citrate) (POC)/hydroxyapatite-based orthopedic fixation devices represents a translational research milestone for biomaterial science. POC joins a short list of biodegradable synthetic polymers that have ever been authorized by the FDA for use in humans. The clinical success of POC has sparked enthusiasm and accelerated the development of next-generation citrate-based biomaterials. This review presents a comprehensive, forward-thinking discussion on the pivotal role of citrate chemistry and metabolism in various tissue regeneration and on the development of functional citrate-based metabotissugenic biomaterials for regenerative engineering applications.