Matthew L. Becker

Conjugating precise concentrations of bioactive peptides on aligned topographies holds a promising application in directionally guiding Schwann cell migration, a significant step in peripheral nerve regeneration. To harness this behavior, we have developed aligned fiber scaffolds functionalized with variable concentration gradients of YIGSR, a laminin-derived peptide known to promote Schwann cell motility. Using thiol-ene click chemistries, we generated uniform and gradient patterns of YIGSR on the aligned fibers with spatial control over tethered peptide concentration during fabrication, yielding two uniform concentration scaffolds of 100 pmol/cm² and 420 pmol/cm² YIGSR, and three gradient profiles of slopes 7 pmol·(cm²·mm)⁻¹, 15 pmol·(cm²·mm)⁻¹, and 60 pmol·(cm²·mm)⁻¹. Schwann cell migration on scaffolds revealed that uniform YIGSR functionalization enhanced migration in a sex-specific and concentration-dependent manner. Female Schwann cells responded with greater migration on 100 pmol/cm² uniform YIGSR-functionalized fibers while male Schwann cell migration was enhanced on fibers with both 100 and 420 pmol/cm² compared to non-functionalized fibers. However, guidance of cell migration can not be achieved with increasing cell speed alone. Therefore, gradients were fabricated directly on the fiber scaffolds and quantified. While shallow YIGSR gradients (7 and 15 pmol·(cm²·mm)⁻¹) did not consistently bias Schwann cell directionality in the direction of the gradient, 60 pmol·(cm²·mm)⁻¹ gradient profiles induced a haptotactic response, measured by directional velocity and haptotactic index, with both sexes migrating toward regions of higher peptide concentration. Thus, along with contact guidance effects provided by aligned fibers, precisely-defined peptide-functionalized gradients can be used to further bias Schwann cell migration for nerve regenerative applications. STATEMENT OF SIGNIFICANCE: Peripheral nerve injuries often result in incomplete recovery, partly because cells crucial for repair cannot efficiently move into injury sites. While researchers have developed aligned fibers that act as a pathway for the cells into the injury site, cells are free to move in any direction along the path, reducing their ability to support repair. This study demonstrates that by combining aligned fibers with bound chemical gradients to act as guard rails, cells move preferentially in one direction along the pathway. By precisely controlling both the fibers' physical alignment and chemical gradients, we achieved unidirectional cell migration. This dual-cue approach represents a significant advancement in biomaterial design for nerve repair, offering a promising strategy to enhance regeneration across nerve defects.

ABSTRACT Selective oxygen permeability coupled with low water vapor transmission is essential for biomedical and packaging applications requiring controlled oxygen flux under humid conditions. However, most high‐performance barrier polymers depend on perfluoroalkyl substances (PFAS), whose persistence and regulatory restrictions limit their long‐term applicability. We designed a series of stereocontrolled thiol‐yne‐based polyesters, including both fluorinated and non‐fluorinated variants, for selective oxygen permeability with considerable water barrier performance. Tailoring polymer crystallinity and morphology tuned both oxygen transport and mechanical properties. Fluorinated polymers demonstrated enhanced hydrophobicity and water resistance while maintaining oxygen diffusivity within a range relevant to oxygen‐sensing applications. Structure–property relationships were elucidated through small‐ and wide‐angle X‐ray scattering, revealing semi‐crystalline domains influenced by fluorine content and dithiol chain length. Barrier performance was rigorously evaluated via water vapor transmission rate and dynamic vapor sorption, showing reduced water uptake with increasing dithiol monomer length and crystallinity. This work introduces a PFAS‐free alternative to conventional barrier materials and establishes a tunable materials platform with potential relevance for biomedical devices and packaging systems requiring controlled oxygen permeability.

Poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) is a stealth polymer that does not exhibit polyethylene glycol (PEG) antigenicity. Herein, we engineered self-assembling nanoparticles composed entirely of POEGMA by designing AB diblock copolymers with varying oligo(ethylene glycol) (EG) side chains. We found that a one-unit difference between di- and tri-ethylene glycol side chains is sufficient to induce amphiphilicity and enables temperature-triggered self-assembly above room temperature when the block length ratio is at least 0.25. To broaden the temperature stability window, we increased amphiphilicity by incorporating mono-ethylene glycol into the hydrophobic block via random copolymerization, yielding nanoparticles stable between 20°C-40°C. These POEGMA nanoparticles effectively encapsulate diverse hydrophobic drugs with high loading efficiency. Notably, POEGMA-encapsulated doxorubicin retained the drug's in vitro activity and exhibited enhanced in vivo efficacy compared to free doxorubicin due to improved pharmacokinetics. Furthermore, these nanoparticles demonstrated stealth behavior by evading recognition by anti-PEG antibodies. This study introduces a versatile, fully POEGMA-based platform for stealth drug delivery with tunable thermal responsiveness and high therapeutic potential.

Primary sensory neurons in dorsal root ganglia (DRG) have long axons and a high demand for mitochondria, and mitochondrial dysfunction has been implicated in peripheral neuropathy after diabetes and chemotherapy1,2. However, the mechanisms by which primary sensory neurons maintain their mitochondrial supply remain unclear. Satellite glial cells (SGCs) in DRG encircle sensory neurons and regulate neuronal activity and pain3. Here we show that SGCs are capable of transferring mitochondria to DRG sensory neurons in vitro, ex vivo and in vivo by the formation of tunnelling nanotubes with SGC-derived myosin 10 (MYO10). Scanning and transmission electron microscopy revealed tunnelling nanotube-like ultrastructures between SGCs and sensory neurons in mouse and human DRG. Blockade of mitochondrial transfer in naive mice leads to nerve degeneration and neuropathic pain. Single-nucleus RNA sequencing and in situ hybridization revealed that MYO10 is highly expressed in human SGCs. Furthermore, SGCs from DRG of people with diabetes exhibit reduced MYO10 expression and mitochondrial transfer to neurons. Adoptive transfer of human SGCs into the mouse DRG provides MYO10-dependent protection against peripheral neuropathy. This study uncovers a previously unrecognized role of peripheral glia and provides insights into small fibre neuropathy in diabetes, offering new therapeutic strategies for the management of neuropathic pain. Mitochondria that are transported from satellite glial cells in dorsal root ganglia to peripheral sensory neurons through tunneling nanotube-like structures provide protection against peripheral neuropathy.

High Resolution Image Download MS PowerPoint Slide Opioids are widely considered to be one of the most effective pain management strategies, but current prescription and distribution models have resulted in high rates of misuse, addiction, and overdose. An alternative to the systemic delivery of opioids is drug-loaded patches for transdermal delivery, currently clinically used with lidocaine and fentanyl. However, significant active pharmaceutical ingredients (API) often remain in the patches at the end of their useful lifetime. Herein, we report the use of oxycodone-loaded, biodegradable amino acid–based poly(ester urea) (PEU) films with thermally driven release behavior. Oxycodone load was varied to achieve a near-physiological glass transition temperature ( T g ), and greater oxycodone release was achieved at temperatures approaching and above the material’s T g . Pharmacokinetic data from an in vivo mouse model incorporating a transdermal application of oxycodone-loaded PEU patches demonstrated no detectable passive release of oxycodone in the plasma. Tissue analysis of the skin surrounding the patch determined there were over 4-fold greater oxycodone levels in the skin than those found following a subcutaneous injection of oxycodone after 24 h. To achieve higher oxycodone release by targeting the thermally driven release behavior in a transdermal setup, microheaters were fabricated by aerosol jet printing of silver nanowires. Oxycodone release doubled in a Franz cell experiment with the use of microheaters, demonstrating significant thermally driven release. This work showcases the temperature-accelerated drug release behavior of oxycodone from PEU films and the future potential for transdermal drug delivery using microheaters.

Current clinical pain management strategies rely heavily on orally prescribed opioids, especially oxycodone, as opposed to non-steroidal anti-inflammatory drugs (NSAIDs) or local anesthetics. Implanted devices that facilitate controlled, localized delivery of NSAIDs could sustain higher drug concentrations at the surgical site and extend pain management efficacy beyond oral or intravenous methods. Meloxicam-loaded poly(ester urea) (PEU) nanofibers are fabricated with variations in polymer molecular mass, additives, additive loads, and substrate thickness to assess their respective influence on sustained meloxicam release. Nanofiber mats loaded with meloxicam and sodium bicarbonate demonstrated superior pain inhibition for three days over intraperitoneal (IP) and intramuscular (IM) injections of meloxicam in a murine tibial fracture pain model. Biopsies of muscle tissue surrounding the fracture, one day post-treatment, possessed high meloxicam concentrations relative to plasma and significantly reduced Ptgs2 expression and COX-2 inhibition. This work demonstrates the extended performance of local meloxicam-loaded PEU implants with significant pain and inflammation suppression.

Glycosylation regulates immune and neural functions within the central nervous system (CNS), yet biomaterials rarely leverage glycans due to their structural complexity. Polysialic acid (PSA), comprising α2,8-linked sialic acid residues, is a promising candidate owing to its potent immunomodulatory interactions with inhibitory Siglec receptors. Systematic screening of multiple sialic acid derivatives identifies PSA as uniquely effective in inducing anti-inflammatory polarization of bone marrow-derived macrophages (BMDMs). Based on these findings, an injectable microporous annealed particle (MAP) scaffold presenting PSA covalently via its reducing end (MAP-PSA) is engineered, recapitulating physiological glycan orientation. MAP-PSA exhibits robust mechanical properties, stable glycan immobilization, and resistance to enzymatic degradation. Using ischemic stroke as a CNS injury model, MAP-PSA significantly reduces neutrophil infiltration and inflammatory activation while enhancing reparative macrophage and microglial phenotypes. These immunomodulatory effects persist into subacute stages, characterized by sustained reductions in inflammation and enhanced microglial homeostasis. Overall, MAP-PSA scaffolds demonstrate a novel therapeutic paradigm for CNS injuries such as stroke, with translational potential for broader neuroinflammatory and regenerative applications.

Background: Brain regeneration after injury is a challenge being tackled by numerous therapeutic strategies in pre-clinical development. There is growing interest in scaffolds implanted in brain lesions. Developments in 3D printing offer the possibility of designing complex structures of varying compositions adapted to tissue anatomy. Methods: This feasibility study assessed the cerebral biocompatibility of four bioeliminable Digital Light Processing (DLP) printed materials in the rat model: gelatin methacrylate (GelMA), poly(ethylene glycol)diacrylate (PEGDA) mixed with GelMA (PEGDA-GelMA), poly(trimethylene carbonate) trimethacrylate (PTMC-tMA) and an ABA triblock copolymer of polypropylene fumarate-b-poly γ-methyl ε-caprolactone-b-polypropylene fumarate (P(PF-MCL-PF)). Their tolerance was compared to that of polydioxanone Ethicon (PDSII), a neurosurgery suture component commonly used in clinical practice. A one-month MRI and behavioral follow-up aided in safety assessment. Results: High-resolution T2 MRI imaging effectively captured the scaffold structures and demonstrated its non-invasive utility in monitoring degradability. PDSII served as a control of the acceptable inflammatory response to implantable foreign bodies. GelMA, PEGDA-GelMA and PTMC-tMA did not affect the permissive glial barrier, promoted cell migration, and neovascularization without additional perilesional microglial inflammation (median mean of 6.5 %, compared to 8.2 % for the PDSII control). However, the GelMA scaffold core was not colonized and allowed a limited neuronal progenitors recruitment. The rigidity of PTMC-tMA facilitated insertion, but posed histological issues. The brain hardly reacted to the P(PF-MCL-PF). Conclusion: All these materials can serve as a basis for brain regeneration. PEGDA-GelMA emerged as a promising candidate for intracerebral implantation, combining biophysical and bioprinting advantages while maintaining an acceptable level of inflammation compared with clinically used suture, paving the way for innovative therapies.

Sexual dimorphism has been observed in many physiological and pathological responses, yet few studies incorporate both female and male experimental groups for preclinical work. For the development of biomaterial devices, in vitro studies are essential for design and optimization, and quantitative comparison of female and male cell migratory behavior is a crucial design consideration. In this work, we thoroughly examined sex-based migration on flat controls and aligned nanofiber scaffolds of various diameters using anomalous and random walk models. Male and female cells exhibited significantly different migration on flat substrates, with female cells having increased speed while male cells had higher persistence. Persistence increased with the introduction of aligned fiber topography for female cells, but only affected male cells on the highest fiber diameter. Speed along the axis of alignment differed between sexes on 1.2 and 1.8 µm fibers. Morphological analysis confirmed cell shape was a function of both sex and fiber size. These results provided critical information regarding sex-based cell migration, highlighting the importance of sex within in vitro studies for clinical device design.

Barrier polymers underpin almost every commercial sector, yet the needs of several emerging areas remain unmet by commercially-available materials, including temporary orthopedic implants, transient health monitors, neural implants, and other long-term implants. The ability to tune polymer composition independently of polymer structure positions thiol-yne click chemistry as a promising platform to serve these emerging technologies. This work describes the differences in the hierarchical structure of stoichiometrically identical materials which differ only in the proportion of the cis versus trans backbone alkene stereochemistry. Varying the isomer content in this way directs different temperature and rate dependent crystallization behavior, which affords control over micron-scale structure. This investigation focuses on how these stereochemical features affect the water vapor permeation process by several methods and develops an understanding of how this unique structural regularity improves barrier performance relative to a commercially available water barrier polymer, poly(ethylene terephthalate).

Peripheral nerve injuries remain a significant clinical challenge, with limited tools available to physicians and patients. Although autografts are the gold standard for nerve reconstruction, they are limited by donor-site morbidity and availability. Commercially available nerve guidance conduits offer alternatives, yet their clinical application remains largely restricted to short nerve gaps with limited success beyond 1 cm. This review provides a summary of the clinical studies on nerve injury repair using commercial nerve guidance conduits and discusses the shortcomings of such devices, including suboptimal mechanical properties, lack of internal guidance structures and bioactivity, and insufficient clinical data. To address these challenges, emerging innovations, such as biofunctionalized materials, conductive scaffolds, and topographically engineered architectures, are readily being explored to improve regenerative outcomes following neural injury. Overall, this work highlights the gaps in commercial devices utilized clinically and brings attention to the evolving landscape of biomaterials research that can transform clinical nerve repair.

Introduction Periprosthetic joint infections are relatively rare complications of total joint replacements. The standard of care for these infections involves the placement of a temporary spacer made of poly (methyl methacrylate) (PMMA) bone cement combined with antibiotics. The rate of major complication can be as high as 12% for PMMA spacers. Therefore, this study was designed to identify an alternative resin material that could be 3D printed, provide mechanical support necessary for ambulation, and deliver a therapeutic dose of antibiotics over an extended period. Methods Test substrates were photochemically printed out of Biomed Clear (BMC) loaded with up to 16% gentamicin or 10% vancomycin (wt%). PMMA and BMC composites were characterized using differential scanning calorimetry, dynamic mechanical analysis, compression testing, and a 30-day antibiotic elution study. Results The thermoset properties of the BMC allowed for the compressive properties to remain unchanged (post-elution = compressive strength 84–94 MPa) as antibiotics were added to the resin (0–16 wt%). However, antibiotic elution was influenced by the type and concentration of the antibiotic in the composite. In contrast, the thermoplastic properties of PMMA led to a decrease in compressive properties with the addition of antibiotics, but PMMA was able to elute relatively more antibiotics. Discussion This study described a novel method to 3D print load bearing materials that can release antibiotics over 30 days. BMC composites have some advantages and disadvantages compared to PMMA that need to be considered when developing new treatments for orthopaedic infections.

Abstract Vertebral body compression fractures are a major cause of chronic back pain, particularly in older adults. Augmentation is currently performed by injecting a poly(methyl methacrylate) (PMMA) slurry of polymer, monomer, and initiator mixed with barium sulfate (BaSO 4 ) into the vertebrae, which then polymerizes in vivo. Herein, a solvent‐free polymer system using poly(allyl glycidyl ether succinate) (PAGES) is developed for vertebral augmentation. PAGES crosslinks in situ through thiol‐ene click chemistry with a cure time at 37 °C ranging from 17 to 53 min based on degree of polymerization and crosslinker concentration. The addition of SrCO 3 increased the ultimate compressive strength (σ max ) of the PAGES composite to 4.4 ± 0.4 MPa. Furthermore, SrCO 3 increases osteoblast proliferation and differentiation of mesenchymal stem cells seeded onto the surface of PAGES composite. Finally, the compressive strength of fractured vertebrae is increased in an ex vivo surrogate rabbit model when filled with injected PAGES composite, demonstrating its potential as a bone augmentation material.

Rib fractures are common among blunt chest trauma patients and are a hallmark of severe thoracic injury with high morbidity and mortality rates. The standard treatment of most rib fracture cases is limited to pain control and respiratory support, with the surgical stabilization of rib fractures (SSRF) using titanium plates reserved for severely injured patients. Although SSRF has been shown to improve long-term patient outcomes, its expanded use has been limited by the invasiveness of the procedure and a lack of safe and effective resorbable fixation materials. While resorbable metal and polymeric plates have each been used in the clinic, many failures have been reported and challenges remain to control the mechanical properties of the plate during the degradation process. The 3D printing of resorbable, fumarate-based copolyester-hydroxyapatite (HAp) composite osteosynthetic plates for use in SSRF is presented, and assess their efficacy in vivo in a rabbit rib fracture model. Compared to rigid titanium fixation plates, ribs fixed with 3D printed composite plates elicit fracture calluses with decreased inflammatory response, enhanced osseointegration, and bone morphometry at 2- and 4-weeks post-fracture comparable to clinically used titanium plates.

Granular hydrogel scaffolds composed of many discrete hydrogel microparticles (HMPs) have demonstrated significant advantages over bulk hydrogels, including injectability and the flexibility to incorporate diverse chemistries, physical properties, and bioactive payloads. Herein, we demonstrate the ability to tune HMP properties through varying the length of poly(ethylene glycol) (PEG) arms and stereocomplexed poly(lactic acid) (SC PLA) cross-links within PEG-based HMPs to further understand the networks' structure-property relationships and utility in a model prodrug delivery system. DSC and WAXS revealed that hydrogels with shorter PEG arms were able to form stereocomplex domains to a greater extent than longer PEG arms. Additionally, as the SC PLA length increased, the HMPs were more thermally and mechanically stable. HMPs were also loaded with model prodrug, doxorubicin, to characterize compositional variations' effects on release profiles. These studies suggest that variations in the cross-linker concentration influence the crystallinity of each HMP formulation, allowing for tunable drug loading and release.

Droplet manipulation technologies play a critical role in many aspects of biochemical research, including in complex reaction assays useful for drug delivery, for building artificial cells, and in synthetic biology. While advancements have been made in manipulating liquid droplets, the capability to freely and dynamically manipulate solid objects across aqueous and oil phases remains unexplored. Here, we develop an acoustofluidic frequency-associated microsphere embedding platform, which enables microscale rapid injection of microparticles from a fluorinated oil into aqueous droplets. By observing different embedding mechanisms at low and high acoustic frequencies, we establish a theoretical model and practical principles for cross-phase manipulations. The proposed system not only enables multi-phase manipulation but also provides contactless control of specific microparticles within various distinctive phases. We demonstrate the acoustic-driven embedding and subsequent on-demand disassembly of hydrogel microspheres. This system indicates potential for reagent delivery and molecule capture applications. It enhances existing droplet manipulation technologies by enabling both multi-phase and cross-phase operations, paving the way for solid-liquid interaction studies in artificial cell research. The capability for intricate multi-phase loading, transport, and reactions offers promising implications for various fields, including in-droplet biochemical assays, drug delivery, and synthetic biology. Cross-phase manipulation holds potential for applications in synthetic biology and drug delivery. Here, authors present an acoustofluidic platform that enables rapid embedding of microparticles from an oil phase into aqueous droplets, offering an effective tool for studying cellular multiphase interactions and related phenomena.

I n the original publication, the H&E staining image for the Rifampicin group in Figure 8E was incorrectly duplicated as the CCO2-64% group.The corrected Figure 8E below now accurately displays the H&E staining of the Rifampicin group.The conclusions remain valid since the wound analysis relied on the complete data set in Figure S64.

Stimuli-responsive drug delivery systems have expanded the diversity of potential cargos by protecting payloads, extending circulation, and controlling payload release. However, quantitative characterization methods that accurately describe these complex systems are needed to accelerate their translation to the clinic. To this extent, degradable, thermoresponsive polyesters were developed through the ring-opening copolymerization of maleic anhydride and an oligo(ethylene glycol)-functionalized epoxide. The resulting polymers possess a lower critical solution temperature such that they are soluble in aqueous solutions at low temperatures (4-7 °C) but assemble into particles above room temperature (25 °C). The particle size and morphology were tunable through the selection of polymer initiator, forming nanoparticle (ca. 162 nm) and microparticle (ca. 1.85 μm) assemblies using macromolecular polyethylene glycol and small molecule propargyl alcohol initiators, respectively. Diffusion-ordered NMR spectroscopy (DOSY) was used over a range of temperatures to develop molecular weight calibrations using certified poly(ethylene glycol) standards. DOSY was able to monitor the dynamic self-assembly behavior of the thermoresponsive polymers in aqueous solutions, and through distinct diffusion constant shifts, quantify the aggregation number of particle intermediates within the nano- and microparticles.

Antimicrobial peptides (AMPs) and synthetic topologically defined peptide mimics have been developed as alternatives to traditional small-molecule antibiotics. AMP mimetics arising from linear polymers used widely in preclinical studies have shown promise but have limited stability. Oligomers possessing cyclic topology have been proposed to have increased stability but remain understudied due to synthetic challenges and concerns over cytotoxicity. Herein, we present an efficient approach to prepare cationic, cyclic oligo(disulfide)s ( CCOs ) from lipoic acid derivatives. The CCOs are obtained in a one-pot cascade reaction of ring-opening polymerization preceding an in situ cyclo-depolymerization. CCOs are effective against a broad spectrum of bacteria, exhibiting a 5.43-log reduction in 5 min against Escherichia coli . They did not induce antimicrobial resistance during 24 successive passages in vitro. The cytotoxicity of CCOs is reduced by exploiting glutathione-triggered degradation. Further, fine-tuning of the cationic-to-hydrophilic ratio in CCOs has yielded improved stability in serum and a high selective index (HC 50 /MIC > 1280) against methicillin-resistant Staphylococcus aureus . In an infected wound rodent model, CCOs have shown substantial antibacterial potency against S. aureus, underscoring their therapeutic potential as a new class of antimicrobial agents.

Mesh suture is an emerging technology for closing high-tension soft tissue wounds. However, bulky mesh surgical knots can irritate surrounding tissue and harbor bacteria, leading to an increased risk of infection and palpability. Thus, a degradable knotless anchoring system is needed to secure mesh sutures. Here, novel anchor clip devices are fabricated via continuous liquid interface production (CLIP) three-dimensional (3D) printing using poly(propylene fumarate- co -propylene succinate) (PPFPS) oligomers. Thiol–ene cross-linking yields fully degradable thermoset devices with tunable mechanical properties. For comparison, high-resolution anchor clips are also fabricated via traditional injection molding using poly( l -lactide- co -glycolide) (PLGA). The PLGA anchor clips show similar mechanical performance to predicate soft tissue fixation techniques in a benchtop abdominal wall reconstruction model. Both PLGA and PPFPS anchor clips demonstrate satisfactory in vivo biocompatibility in a porcine abdominal implantation model. This work outlines the development of bioresorbable anchor clips for soft tissue fixation and illustrates their potential for clinical translation.

Mechanical bonds arise between molecules that contain interlocked subunits, such as one macrocycle threaded through another. Within polymers, these linkages will confer distinctive mechanical properties and other emergent behaviors, but polymerizations that form mechanical bonds efficiently and use simple monomeric building blocks are rare. In this work, we introduce a solid-state polymerization in which one monomer infiltrates crystals of another to form a macrocycle and mechanical bond at each repeat unit of a two-dimensional (2D) polymer. This mechanically interlocked 2D polymer is formed as a layered solid that is readily exfoliated in common organic solvents, enabling spectroscopic characterization and atomic-resolution imaging using advanced electron microscopy techniques. The 2D mechanically interlocked polymer is easily prepared on multigram scales, which, along with its solution processibility, enables the facile fabrication of composite fibers with Ultem that exhibit enhanced stiffness and strength.

Safe, effective pain management remains one of the biggest challenges following surgical procedures. Despite widespread recognition of this problem and advances in the mechanistic understanding of pain signaling, post-surgical pain is often undermanaged, with opioid use remaining the clinical standard. As an alternative to current oral, systemic treatments, a degradable bupivacaine-loaded poly(ester urea) (PEU) thin film has been developed to deliver bupivacaine directly to the site of injury over an extended duration. The dose and duration of bupivacaine delivery is controlled using polymer composition and bupivacaine concentration. Systemic bupivacaine concentrations are more than an order of magnitude lower when delivered locally versus intravenous injection. Tissue analysis showed that the majority of bupivacaine is deposited into subcutaneous tissue directly surrounding the implant. Bupivacaine concentration in soft tissue around the implant are 30-fold higher than plasma values, indicating that release from PEU implants remains localized. Bupivacaine-loaded PEU films are assessed into two established mouse models for diabetic neuropathic pain and post-surgical incisional pain. In each model, bupivacaine eluting PEU films effectively block pain for 3-5 days before returning to baseline levels without loss of motor function and without signs of neurotoxicity.

Poly(ε-caprolactone) (PCL) is a widely utilized polymer within the biomedical field; however, one of its limitations is the multi-year long degradation profile. Herein, we report a semiaromatic polyester-ether (SAEE) PCL copolymer using a salicylic acid–based monomer which can disrupt the semicrystalline nature of the bulk material. The molar percentage of incorporation correlated to a linear decrease in melting and crystallization temperature, until a totally amorphous solid was seen at 37 mol %. Alongside this, mechanical analysis elucidated a softer, more extensible material with E ′ decreasing from 292 to 222 to 43.8 MPa for PCL to 10 to 22 mol % SAEE, respectively. Accelerated basic degradation studies (2 M NaOH) exhibited total mass loss after 16 weeks for 6 mol % compared to only 38% mass loss for PCL over the same period. Overall, by varying the SAEE mol %, we show the ability to finely tune the thermal, mechanical, and degradation profiles of PCL copolymers while maintaining an advantageous biological profile.

Barrier membranes (BM) for guided bone regeneration (GBR) aim to support the osteogenic healing process of a defined bony defect by excluding epithelial (gingival) ingrowth and enabling osteoprogenitor and stem cells to proliferate and differentiate into bone tissue. Currently, the most widely used membranes for these approaches are collagen-derived, and there is a discrepancy in defining the optimal collagen membrane in terms of biocompatibility, strength, and degradation rates. Motivated by these clinical observations, we designed a collagen-free membrane based on l -valine- co - l -phenylalanine-poly(ester urea) (PEU) copolymer via electrospinning. Degradation and mechanical properties of these membranes were performed on as-spun and water-aged samples. Alveolar-bone-derived stem cells (AvBMSCs) were seeded on the PEU BM to assess their cell compatibility and osteogenic characteristics, including cell viability, attachment/spreading, proliferation, and mineralized tissue-associated gene expression. In vivo, PEU BMs were subcutaneously implanted in rats to evaluate their potential to cause inflammatory responses and facilitate angiogenesis. Finally, critical-size calvarial defects and a periodontal model were used to assess the regenerative capacity of the electrospun PEU BM compared to clinically available Cytoflex synthetic membranes. PEU BM demonstrated equal biocompatibility to Cytoflex with superior mechanical performance in strength and elasticity. Additionally, after 14 days, PEU BM exhibited a higher expression of BGLAP/osteocalcin and superior in vivo performance–less inflammation and increased CD31 and VWF expression over time. When placed in critical-sized defects in the calvaria of rats, the PEU BM led to robust bone formation with high expression of osteogenesis and angiogenesis markers. Moreover, our membrane enhanced alveolar bone and cementum regeneration in an established periodontal model after 8 weeks. We demonstrate that the PEU BM exhibits favorable clinical properties, including mechanical stability, cytocompatibility, and facilitated bone formation in vitro and in vivo. This highlights its suitability for GBR in periodontal and craniofacial bone defects.

Affinity precipitation is a powerful separation method in that it combines the binding selectivity of affinity chromatography with precipitation of captured biomolecules via phase separation triggered by small changes in the environment, e.g., pH, ionic strength, temperature, light, etc. Elastin-like polypeptides (ELPs) are thermally responsive biopolymers composed of pentapeptide repeats VPGVG that undergo reversible phase separation, where they aggregate when temperature and/or salt concentration are increased. Here we describe the generation of an ELP fusion to a soluble streptavidin mutant that enables rapid purification of any Strep-tag II fusion protein of interest. This heterobifunctional protein takes advantage of the native tetrameric structure of streptavidin, leading to binding-induced multivalent crosslinking upon protein capture. The efficient biotin-mediated dissociation of the bound Strep-tag II fusion protein from the streptavidin-ELP capturing scaffold allows for mild elution conditions. We also show that this platform is particularly effective in the purification of a virus-like particle (VLP)-like E2 protein nanoparticle, likely because the high valency of the protein particle causes binding-induced crosslinking and precipitation. Considering the importance of VLP for gene therapy applications, we believe this is a particularly exciting advance. We demonstrated this feasibility by the efficient purification of a VLP-like E2 protein nanoparticle as a surrogate.

BACKGROUND: Rib fractures are a common traumatic injury affecting more than 350,000 patients a year. Early stabilization has shown to be effective in reducing pulmonary complications. Platelet-rich plasma (PRP) is a growth factor-rich blood product known to improve soft tissue and bone healing. We hypothesized that the addition of PRP to a rib fracture site would accelerate callus formation and improve callus strength. METHODS: Platelet-rich plasma was isolated from pooled Lewis rat blood and quantified. Thirty-two Lewis rats underwent fracture of the sixth rib and were treated with 100 μL PRP (1 × 10 6 platelets/μL) or saline. At 2 weeks, ribs were harvested and underwent a 3-point bend, x-ray, and microcomputed tomography, and callus sections were stained with 4',6-diamidino-2-phenylindole and Alcian blue and picrosirius red. At 6 weeks, ribs were harvested and underwent a 3-point bend test, x-ray, microcomputed tomography, and Alcian blue and picrosirius red staining. RESULTS: At 2 weeks, PRP increased callus diameter (9.3 mm vs. 4.3 mm, p = 0.0002), callus index (4.5 vs. 2.1, p = 0.0002), bone volume/total volume (0.0551 vs. 0.0361, p = 0.0024), cellularization (2,364 vs. 1,196, p < 0.0001), and cartilage (12.12% vs. 3.11%, p = 0.0001) and collagen (6.64% vs. 4.85%, p = 0.0087) content compared with controls. At 6 weeks, PRP increased fracture callus diameter (5.0 mm vs. 4.0 mm, 0.0466), callus index (2.5 vs. 2.0, p = 0.0466), BV/TV (0.0415 vs. 0.0308, p = 0.0358), and higher cartilage (8.21% vs. 3.26%, p < 0.0001) and collagen (37.61% vs. 28.00%, p = 0.0022) content compared with controls. At 6 weeks, PRP samples trended toward improved mechanical characteristics; however, these results did not reach significance ( p > 0.05). CONCLUSION: Rib fractures are a common injury, and accelerated stabilization could improve clinical outcomes. Platelet-rich plasma significantly increased callus size, calcium deposition, and cartilage and collagen content at 2 and 6 weeks and trended toward improved strength and toughness on mechanical analysis at 6 weeks compared with controls, although this did not reach significance. These findings suggest that PRP may be a useful adjunct to accelerate and improve fracture healing in high-risk patients.

Digital light processing (DLP) printing forms solid constructs from fluidic resins by photochemically crosslinking polymeric resins with reactive functional groups. DLP is used widely due to its efficient, high-resolution printing, but its use and translational potential has been limited in some applications as state-of-the-art resins experience unpredictable and anisotropic part shrinkage due to the use of solvent needed to reduce resin viscosity and layer dependent crosslinking. Herein, poly(allyl glycidyl ether succinate) (PAGES), a low viscosity, degradable polyester, was synthesized by ring opening copolymerization and used in combination with degradable thiol crosslinkers to afford a solvent free resin that can be utilized in DLP printing. Varying resin formulations of PAGES polymer are shown to decrease part shrinkage from 14 % to 0.3 %. Photochemically printed parts fabricated from PAGES possess tensile moduli between 0.43 and 6.18 MPa and degradation profiles are shown to vary between 12 and 40 days under accelerated conditions based on degree of polymerization and crosslink ratio.

Abstract Digital light processing (DLP) printing forms solid constructs from fluidic resins by photochemically crosslinking polymeric resins with reactive functional groups. DLP is used widely due to its efficient, high‐resolution printing, but its use and translational potential has been limited in some applications as state‐of‐the‐art resins experience unpredictable and anisotropic part shrinkage due to the use of solvent needed to reduce resin viscosity and layer dependent crosslinking. Herein, poly(allyl glycidyl ether succinate) (PAGES), a low viscosity, degradable polyester, was synthesized by ring opening copolymerization and used in combination with degradable thiol crosslinkers to afford a solvent free resin that can be utilized in DLP printing. Varying resin formulations of PAGES polymer are shown to decrease part shrinkage from 14 % to 0.3 %. Photochemically printed parts fabricated from PAGES possess tensile moduli between 0.43 and 6.18 MPa and degradation profiles are shown to vary between 12 and 40 days under accelerated conditions based on degree of polymerization and crosslink ratio.

Microneedle array patches (MAPs) are extensively studied for transdermal drug delivery. Additive manufacturing enables precise control over MAP customization and rapid fabrication. However, the scope of 3D-printable, bioresorbable materials is limited. Dexamethasone (DXM) is widely used to manage inflammation and pain, but its application is limited by systemic side effects. Thus, it is crucial to achieve high local drug concentrations while maintaining low serum levels. Here, poly(propylene fumarate-co-propylene succinate) oligomers are fabricated into DXM-loaded, bioresorbable MAPs via continuous liquid interface production 3D printing. Thiol-ene click chemistry yields MAPs with tailorable mechanical and degradation properties. DXM-loaded MAPs exhibit controlled elution of drug in vitro. Transdermal application of DXM-loaded MAPs in a murine tibial fracture model leads to substantial relief of postoperative pain. Pharmacokinetic analysis shows that MAP administration is able to control pain at a significantly lower dose than intravenous administration. This work expands the material properties of 3D-printed poly(propylene fumarate-co-propylene succinate) copolyesters and their use in drug delivery applications.

Abstract Vat photopolymerization 3D printing has proven very successful for the rapid additive manufacturing (AM) of polymeric parts at high resolution. However, the range of materials that can be printed and their resulting properties remains narrow. Herein, we report the successful AM of a series of poly(carbonate‐ b ‐ester‐ b ‐carbonate) elastomers, derived from carbon dioxide and bio‐derived ϵ‐decalactone. By employing a highly active and selective Co(II)Mg(II) polymerization catalyst, an ABA triblock copolymer ( M n =6.3 kg mol −1 , Ð M =1.26) was synthesized, formulated into resins which were 3D printed using digital light processing (DLP) and a thiol‐ene‐based crosslinking system. A series of elastomeric and degradable thermosets were produced, with varying thiol cross‐linker length and poly(ethylene glycol) content, to produce complex triply periodic geometries at high resolution. Thermomechanical characterization of the materials reveals printing‐induced microphase separation and tunable hydrophilicity. These findings highlight how utilizing DLP can produce sustainable materials from low molar mass polyols quickly and at high resolution. The 3D printing of these functional materials may help to expedite the production of sustainable plastics and elastomers with potential to replace conventional petrochemical‐based options.

Abstract Vat photopolymerization 3D printing has proven very successful for the rapid additive manufacturing (AM) of polymeric parts at high resolution. However, the range of materials that can be printed and their resulting properties remains narrow. Herein, we report the successful AM of a series of poly(carbonate‐ b ‐ester‐ b ‐carbonate) elastomers, derived from carbon dioxide and bio‐derived ϵ‐decalactone. By employing a highly active and selective Co(II)Mg(II) polymerization catalyst, an ABA triblock copolymer ( M n =6.3 kg mol −1 , Ð M =1.26) was synthesized, formulated into resins which were 3D printed using digital light processing (DLP) and a thiol‐ene‐based crosslinking system. A series of elastomeric and degradable thermosets were produced, with varying thiol cross‐linker length and poly(ethylene glycol) content, to produce complex triply periodic geometries at high resolution. Thermomechanical characterization of the materials reveals printing‐induced microphase separation and tunable hydrophilicity. These findings highlight how utilizing DLP can produce sustainable materials from low molar mass polyols quickly and at high resolution. The 3D printing of these functional materials may help to expedite the production of sustainable plastics and elastomers with potential to replace conventional petrochemical‐based options.

Hydrogel microparticles (HMPs) have been investigated widely for their use in tissue engineering and drug delivery applications. However, translation of these highly tunable systems has been hindered by covalent cross-linking methods within microparticles. Stereocomplexation, a stereospecific form of physical cross-linking, provides a robust yet degradable alternative for creating translationally relevant HMPs. Herein, 4-arm polyethylene glycol (PEG) stars were used as macromolecular initiators from which oligomeric poly( l -lactic acid) (PLLA) was polymerized with a degree of polymerization (DP n ) of 20 on each arm. Similarly, complementary propargyl-containing ABA cross-linkers with enantiomeric poly( d -lactic acid) (PDLA) segments (DP n = 20) on each arm. Droplets of these gel precursors were formed via a microfluidic organic-in-oil-in-water system where microparticles self-assembled via stereocomplexation and were stabilized after precipitation in deionized water. By varying the flow rate of the dispersed phase, well-defined microparticles with diameters of 33.7 ± 0.5, 62.4 ± 0.6, and 105.7 ± 0.8 μm were fabricated. Gelation due to stereocomplexation was confirmed via wide-angle X-ray scattering in which HMPs exhibited the signature diffraction pattern of stereocomplexed PLA at 2θ = 12.2, 21.2, 24.2°. Differential scanning calorimetry also confirmed stereocomplexation by the appearance of a crystallization exotherm ( T c = 37 °C) and a high-temperature endotherm ( T m = 159 °C) that does not appear in the homocrystallization of PLLA or the hydrogel precursors. Additionally, the propargyl handle present on the cross-linker allows for pre- or post-assembly thiol-yne “click” functionalization as demonstrated by the addition of thiol-containing fluorophores to the HMPs.

Product association of host-cell proteins (HCPs) to monoclonal antibodies (mAbs) is widely regarded as a mechanism that can enable HCP persistence through multiple purification steps and even into the final drug substance. Discussion of this mechanism often implies that the existence or extent of persistence is directly related to the strength of binding but actual measurements of the binding affinity of such interactions remain sparse. Two separate avenues of investigation of HCP-mAb binding are reported here. One is the measurement of the affinity of binding of individual, commonly persistent Chinese hamster ovary (CHO) HCPs to each of a set of mAbs, and the other uses quantitative proteomic measurements to assess binding of HCPs in a null CHO harvested cell culture fluid (HCCF) to mAbs produced in the same cell line. The individual HCP measurements show that the binding affinities of individual HCPs to different mAbs can vary appreciably but are rarely very high, with only weak pH dependence. The measurements on the null HCCF allow estimation of individual HCP-mAb affinities; these are typically weaker than those seen in affinity measurements on isolated HCPs. Instead, the extent of binding appears correlated with the initial abundance of individual HCPs in the HCCF and the forms of the HCPs in the solution, i.e., whether HCPs are present as free molecules or as parts of large aggregates. Separate protein A chromatography experiments performed by feeding different fractions of a mAb-containing HCCF obtained by size-exclusion chromatography (SEC) showed clear differences in the number and identity of HCPs found in the protein A eluate. These results indicate a significant role for HCP-mAb association in determining HCP persistence through protein A chromatography, presumably through binding of HCP-mAb complexes to the resin. Overall, the results illustrate the importance of considering more fully the biophysical context of HCP-product association in assessing the factors that may affect the phenomenon and determine its implications. Knowledge of the abundances and the forms of individual or aggregated HCPs in HCCF are particularly significant, emphasizing the integration of upstream and downstream bioprocessing and the importance of understanding the collective properties of HCPs in addition to just the biophysical properties of individual HCPs.

POLYMERIC MICELLES; POLYMERSOMESThe cover by Eleonora G. Hochreiner represents the process of polymerization-induced self-assembly (PISA) toward pharmaceutical application.Starting from the bottom right with the initial building blocks (hydrophilic polymer and hydrophobic monomer), polymeric micelles are formed upon block copolymer synthesis via PISA and loaded with therapeutic cargo (blue stars).The ultimate goal is application as drug delivery vehicles, which is indicated by the capsules in the top left corner.

<JATS1:p>Encyclopedic in scope, this book offers wide-ranging coverage of the foundational teachings and practices within the mainstream of the classical Christian tradition. It begins with their roots in the Scriptures, and also branches out into Eastern and Western Christianity, ancient, medieval, and modern, to the present-day.</JATS1:p> <JATS1:p>Part I provides an overview of some of these routes, then presents an historical survey of Christianity’s major traditions. Part II unpacks some of the character of that revelation, focusing particularly on epistemological and procedural questions. Finally, Part III looks at Christian theology in a university setting: the possibility and shape of theology as a university discipline, its major subfields, and its relations with humanities and the sciences respectively.</JATS1:p> <JATS1:p>Fundamental Theology: A Protestant Perspective, 2nd edition, includes a wide range of pedagogical features:</JATS1:p> <JATS1:p>- each chapter begins with an outline thesis statement, highlighted in bold</JATS1:p> <JATS1:p>- charts and graphs</JATS1:p> <JATS1:p>- relevant headings and subheadings employed throughout the book</JATS1:p> <JATS1:p>- keywords</JATS1:p> <JATS1:p>- provides a survey of pertinent reference literature</JATS1:p> <JATS1:p>- questions for review and discussion</JATS1:p> <JATS1:p>- annotated suggestions for further reading</JATS1:p>

Resorbable, implantable bioelectronic devices are emerging as powerful tools to reliably monitor critical physiological parameters in real time over extended periods. While degradable magnesium-based electronics have pioneered this effort, relatively short functional lifetimes have slowed clinical translation. Barrier films that are both flexible and resorbable over predictable timelines would enable tunability in device lifetime and expand the viability of these devices. Herein, we present a library of stereocontrolled succinate-based copolyesters which leverage copolymer composition and processing method to afford tunability over thermomechanical, crystalline, and barrier properties. One copolymer composition within this library has extended the functional lifetime of transient bioelectronic prototypes over existing systems by several weeks-representing a considerable step towards translational devices.