Network interactions simultaneously enhance stiffness and lubricity of triple-network hydrogels.

Synthetic hydrogels displaying cartilage-mimetic bulk and surface properties may serve as cartilage substitutes. Multi-network, electrostatic hydrogels that leverage intra- and inter-network repulsive and attractive forces represent a promising approach. Herein, triple network (TN) hydrogels were prepared to obtain a combination of desired characteristics (i.e., hydration, stiffness, shear stress, and friction properties). The TN hydrogels were comprised of a negatively charged 1st network and a neutral 2nd network possessing hydrophobic associations. Presumed to significantly influence surface properties, the 3rd network charge was systematically varied as cationic, anionic, and zwitterionic. A double-network (DN) hydrogel, comprised of the same 1st and 2nd network as for the TN hydrogels, was included as a control as well as native cartilage specimens. Micro-indentation was performed with a steel ball, yielding stiffness values as well as the contact area during sliding. The lubrication in both deionized (DI) water and fetal bovine serum (FBS) was evaluated with the micro-indenter wherein the stage reciprocated in a range of speeds. All the TN hydrogels exhibited greater Youngs modulus than the DN hydrogel control. The TN bearing a cationic 3rd network exhibited an exceptionally high Youngs modulus of ≈1.4 MPa, which was even higher than that of the cartilage samples. In both DI water and FBS, for most testing speeds, the TN hydrogels exhibited lower friction coefficient (COF) values and lower shear stresses than DN hydrogel as well as the native cartilage specimens.

Biocompatibility and Bone Regeneration by Shape Memory Polymer Scaffolds.

Biodegradable, shape memory polymer (SMP) scaffolds based on poly(ε-caprolactone) (PCL) offer unique advantages as a regenerative treatment strategy for critical-sized bone defects. In particular, a conformal fit may be achieved following exposure to warm saline, thereby improving osseointegration and regeneration. Advancing the clinical translation of these SMP scaffolds requires establishment of efficacy not only in non-loading models, but also load-bearing or load-sharing models. Thus, the present study evaluated the biocompatibility and bone regeneration potential of SMP scaffolds in a rabbit distal femoral condyle model. Two distinct SMP scaffold compositions were evaluated, a "PCL-only" scaffold formed from PCL-diacrylate (PCL-DA) and a semi-interpenetrating network (semi-IPN) formed from PCL-DA and poly(L-lactic acid) (PCL:PLLA). Semi-IPN PCL:PLLA scaffolds possess greater rigidity and faster rates of degradation versus PCL scaffolds. In vivo biocompatibility was assessed with a rat subcutaneous implantation model, whereas osseointegration was assessed with a 4 mm × 8 mm rabbit distal femoral condyle defect model. Both types of SMP scaffolds exhibited excellent biocompatibility marked by infiltration with fibrous tissue and a minimal inflammatory response. When implanted in the rabbit distal femur, both SMP scaffolds supported bone ingrowth. Collectively, these results demonstrate that the SMP scaffolds are biocompatible and integrate with adjacent host osseous tissues when implanted in vivo in a load-sharing environment. This study provides key proof-of-concept data necessary to proceed with large animal translational studies and clinical trials in human subjects.

Shape Memory Polymer Bioglass Composite Scaffolds Designed to Heal Complex Bone Defects.

An off-the-shelf scaffold with requisite properties could enable the viable treatment of irregular craniomaxillofacial bone defects. Notably, the scaffold should be conformally fitting, innately bioactive, and bioresorbable. In prior work, we developed a series of shape memory polymer (SMP) scaffolds based on cross-linked poly(ε-caprolactone) (PCL). These were capable of "self-fitting" into complex bone defects when exposed to temperatures above the melt transition of the constituent PCL, either linear-PCL-diacrylate (linear-PCL-DA, Tm ∼55 °C) or star-PCL-tetraacrylate (star-PCL-TA, Tm ∼45 °C) for the potential to improve tissue safety. To achieve favorably increased degradation rates versus PCL-only scaffolds, semi-interpenetrating networks (semi-IPNs) were formed by including linear- or star-poly(l-lactic acid) (PLLA). A potential limitation of these self-fitting scaffolds is the lack of bioactivity, which is essential to osteoinductivity and osseointegration. Herein, analogous composite scaffolds were formed with 45S5 bioglass (BG) to impart bioactivity. The solvent-cast particulate leaching fabrication method was adapted to introduce BG to the fused salt template, resulting in composites with BG concentrated on the pore wall surfaces rather than within pore struts. Composite scaffolds with good pore wall integrity were produced with 2.5, 5, and 10 wt % BG. All composite scaffolds exhibited non-brittle behavior and did not fracture with 85% strain. For semi-IPN composite scaffolds, PLLA crystallinity was lost, and mechanical properties were not appreciably altered versus the non-BG controls. Sufficient retention of PCL crystallinity led to excellent shape memory behavior. The inclusion of 5 and 10 wt % BG led to hydroxyapatite mineralization after 1 day of exposure to simulated body fluid, as well as increased rates of in vitro degradation.

Star-PCL shape memory polymer (SMP) scaffolds with tunable transition temperatures for enhanced utility.

Thermoresponsive shape memory polymers (SMPs) prepared from UV-curable poly(ε-caprolactone) (PCL) macromers have the potential to create self-fitting bone scaffolds, self-expanding vaginal stents, and other shape-shifting devices. To ensure tissue safety during deployment, the shape actuation temperature (i.e., the melt transition temperature or Tm of PCL) must be reduced from ∼55 °C that is observed for scaffolds prepared from linear-PCL-DA (Mn ∼ 10 kg mol-1). Moreover, increasing the rate of biodegradation would be advantageous, facilitating bone tissue healing and potentially eliminating the need for stent retrieval. Herein, a series of six UV-curable PCL macromers were prepared with linear or 4-arm star architectures and with Mns of 10, 7.5, and 5 kg mol-1, and subsequently fabricated into six porous scaffold compositions (10k, 7.5k, 5k, 10k★, 7.5k★, and 5k★) via solvent casting particulate leaching (SCPL). Scaffolds produced from star-PCL-tetraacrylate (star-PCL-TA) macromers produced pronounced reductions in Tm with decreased Mnversus those formed with the corresponding linear-PCL-diacrylate (linear-PCL-DA) macromers. Scaffolds were produced with the desired reduced Tm profiles: 37 °C < Tm < 55 °C (self-fitting bone scaffold), and Tm ≤ 37 °C (self-expanding stent). As macromer Mn decreased, crosslink density increased while % crystallinity decreased, particularly for scaffolds prepared from star-PCL-TA macromers. While shape memory behavior was retained and radial expansion pressure increased, this imparted a reduction in modulus but with an increase in the rate of degradation.

Trends in bioactivity: inducing and detecting mineralization of regenerative polymeric scaffolds.

Due to limitations of biological and alloplastic grafts, regenerative engineering has emerged as a promising alternative to treat bone defects. Bioactive polymeric scaffolds are an integral part of such an approach. Bioactivity importantly induces hydroxyapatite mineralization that promotes osteoinductivity and osseointegration with surrounding bone tissue. Strategies to confer bioactivity to polymeric scaffolds utilize bioceramic fillers, coatings and surface treatments, and additives. These approaches can also favorably impact mechanical and degradation properties. A variety of fabrication methods are utilized to prepare scaffolds with requisite morphological features. The bioactivity of scaffolds may be evaluated with a broad set of techniques, including in vitro (acellular and cellular) and in vivo methods. Herein, we highlight contemporary and emerging approaches to prepare and assess scaffold bioactivity, as well as existing challenges.

High-Throughput Screening of Thiol-ene Click Chemistries for Bone Adhesive Polymers.

Metal surgical pins and screws are employed in millions of orthopedic surgical procedures every year worldwide, but their usability is limited in the case of complex, comminuted fractures or in surgeries on smaller bones. Therefore, replacing such implants with a bone adhesive material has long been considered an attractive option. However, synthesizing a biocompatible bone adhesive with a high bond strength that is simple to apply presents many challenges. To rapidly identify candidate polymers for a biocompatible bone adhesive, we employed a high-throughput screening strategy to assess human mesenchymal stromal cell (hMSC) adhesion toward a library of polymers synthesized via thiol-ene click chemistry. We chose thiol-ene click chemistry because multifunctional monomers can be rapidly cured via ultraviolet (UV) light while minimizing residual monomer, and it provides a scalable manufacturing process for candidate polymers identified from a high-throughput screen. This screening methodology identified a copolymer (1-S2-FT01) composed of the monomers 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (TATATO) and pentaerythritol tetrakis (3-mercaptopropionate) (PETMP), which supported highest hMSC adhesion across a library of 90 polymers. The identified copolymer (1-S2-FT01) exhibited favorable compressive and tensile properties compared to existing commercial bone adhesives and adhered to bone with adhesion strengths similar to commercially available bone glues such as Histoacryl. Furthermore, this cytocompatible polymer supported osteogenic differentiation of hMSCs and could adhere 3D porous polymer scaffolds to the bone tissue, making this polymer an ideal candidate as an alternative bone adhesive with broad utility in orthopedic surgery.

Amphiphilic silicones for the facile dispersion of carbon nanotubes and formation of soft skin electrodes.

Flexible, dry skin electrodes represent a potentially superior alternative to standard Ag/AgCl metal electrodes for wearable devices used in long-term monitoring. Herein, such electrodes were formed using a facile method for dispersing carbon nanotubes (CNTs) in a silicone matrix using custom amphiphilic dispersive additives (DSPAs). Using only brief mixing and without the use of solvents or surface modification of CNTs, twelve poly(ethylene oxide)-silanes (PEO-SAs) of varying crosslinkability, architecture, siloxane tether length, and molar ratio of siloxane:PEO were combined with an addition cure silicone and CNTs. Nearly all PEO-SA modified silicone-CNT composites demonstrated improved conductivity compared to the unmodified composite. Best conductivities correlated to composites prepared with PEO-SAs that formed micelles of particular sizes (d ~ 200 - 300 nm) and coincided to PEO-SAs with a siloxane:PEO molar ratio of ~ 0.75 - 3.00. Superior dispersion of CNT by such PEO-SAs was exemplified by scanning electron microscopy (SEM). Advantageously, modified composites retained their moduli, rather than becoming more rigid. Resultant electrodes fabricated with modified composites showed skin-electrode impedance comparable to that of Ag/AgCl electrodes. Combined, these results demonstrate the potential of silicone-CNT composites prepared with PEO-SA DSPAs as flexible, dry electrodes as a superior alternative to traditional electrodes.

Adhesive Hydrogel Building Blocks to Reconstruct Complex Cartilage Tissues.

Cartilage has an intrinsically low healing capacity, thereby requiring surgical intervention. However, limitations of biological grafting and existing synthetic replacements have prompted the need to produce cartilage-mimetic substitutes. Cartilage tissues perform critical functions that include load bearing and weight distribution, as well as articulation. These are characterized by a range of high moduli (≥1 MPa) as well as high hydration (60-80%). Additionally, cartilage tissues display spatial heterogeneity, resulting in regional differences in stiffness that are paramount to biomechanical performance. Thus, cartilage substitutes would ideally recapitulate both local and regional properties. Toward this goal, triple network (TN) hydrogels were prepared with cartilage-like hydration and moduli as well as adhesivity to one another. TNs were formed with either an anionic or cationic 3rd network, resulting in adhesion upon contact due to electrostatic attractive forces. With the increased concentration of the 3rd network, robust adhesivity was achieved as characterized by shear strengths of ∼80 kPa. The utility of TN hydrogels to form cartilage-like constructs was exemplified in the case of an intervertebral disc (IVD) having two discrete but connected zones. Overall, these adhesive TN hydrogels represent a potential strategy to prepare cartilage substitutes with native-like regional properties.

Biomedical Silicones: Leveraging Additive Strategies to Propel Modern Utility.

Silicones have a long history of use in biomedical devices, with unique properties stemming from the siloxane (Si-O-Si) backbone that feature a high degree of flexibility and chemical stability. However, surface, rheological, mechanical, and electrical properties of silicones can limit their utility. Successful modification of silicones to address these limitations could lead to superior and new biomedical devices. Toward improving such properties, recent additive strategies have been leveraged to modify biomedical silicones and are highlighted herein.

Emerging polymeric material strategies for cartilage repair.

Cartilage is found throughout the body, serving an array of essential functions. Owing to the limited healing capacity of cartilage, damage or degeneration is often permanent and so requires clinical intervention. Established surgical techniques generally rely on biological grafting. However, recent advances in polymeric materials provide an encouraging alternative to overcome limits of auto- and allografts. For regenerative engineering of cartilage, a polymeric scaffold ideally supports and instructs tissue regeneration while also providing mechanical integrity. Scaffolds direct regeneration via chemical and mechanical cues, as well as delivery and support of exogenous cells and bioactive factors. Advanced polymeric scaffolds aim to direct regeneration locally, replicating the heterogeneities of native tissues. Alternatively, new cartilage-mimetic hydrogels have potential to serve as synthetic cartilage replacements. Prepared as multi-network or composite hydrogels, the most promising candidates have simultaneously realized the hydration, mechanical, and tribological properties of native cartilage. Collectively, the recent rise in polymers for cartilage regeneration and replacement proposes a changing paradigm, with a new generation of materials paving the way for improved clinical outcomes.

Silicone-containing thermoresponsive membranes to form an optical glucose biosensor.

Glucose biosensors that could be subcutaneously injected and interrogated without a physically connected electrode and transmitter affixed to skin would represent a major advancement in reducing the user burden of continuous glucose monitors (CGMs). Towards this goal, an optical glucose biosensor was formed by strategically tailoring a thermoresponsive double network (DN) membrane to house a phosphorescence lifetime-based glucose sensing assay. This membrane was selected based on its potential to exhibit reduced biofouling via 'self-cleaning' due to cyclical deswelling/reswelling in vivo. The membrane was strategically tailored to incorporate oxygen-sensitive metalloporphyrin phosphor, Pd meso-tetra(sulfophenyl)-tetrabenzoporphyrin ([PdPh4(SO3Na)4TBP]3) (HULK) and glucose oxidase (GOx). Specifically, electrostatic interactions and colvalent bonds were used to stabilize HULK and GOx within the membrane, respectively. Enhancing the oxygen permeability of the membrane was necessary to achieve sensitivity of HULK/GOx to physiological glucose levels. Thus, silicone microparticles were incorporated at two concentrations. Key properties of SiHy-0.25 and SiHy-0.5 microparticle-containing compositions were compared to a control having no microparticles (SiHy-0). The discrete nature of the silicone microparticles maintained the desired thermosensitivity profile and did not impact water content. While the modulus decreased with silicone microparticle content, membranes were more mechanically robust versus a conventional hydrogel. SiHy-0.25, owing to apparent phase separation, displayed greater glucose diffusion and oxygen permeability versus SiHy-0.5. Furthermore, SiHy-0.25 biosensors exhibited the greatest glucose sensitivity range of 100 to 300 mg dL-1versus only 100 to 150 mg dL-1 for both SiHy-0 and SiHy-0.5 biosensors.

Ultra-High Modulus Hydrogels Mimicking Cartilage of the Human Body.

The human body is comprised of numerous types of cartilage with a range of high moduli, despite their high hydration. Owing to the limitations of cartilage tissue healing and biological grafting procedures, synthetic replacements have emerged but are limited by poorly matched moduli. While conventional hydrogels can achieve similar hydration to cartilage tissues, their moduli are substantially inferior. Herein, triple network (TN) hydrogels are prepared to synergistically leverage intra-network electrostatic repulsive and hydrophobic interactions, as well as inter-network electrostatic attractive interactions. They are comprised of an anionic 1st network, a neutral 2nd network (capable of hydrophobic associations), and a cationic 3rd network. Collectively, these interactions act synergistically as effective, yet dynamic crosslinks. By tuning the concentration of the cationic 3rd network, these TN hydrogels achieve high moduli of ≈1.5 to ≈3.5 MPa without diminishing cartilage-like water contents (≈80%), strengths, or toughness values. This unprecedented combination of properties poises these TN hydrogels as cartilage substitutes in applications spanning articulating joints, intervertebral discs (IVDs), trachea, and temporomandibular joint disc (TMJ).

A Glucose Biosensor Based on Phosphorescence Lifetime Sensing and a Thermoresponsive Membrane.

The adoption of existing continuous glucose monitors (CGMs) is limited by user burden. Herein, a design for a glucose biosensor with the potential for subcutaneous implantation, without the need for a transcutaneous probe or affixed transmitter, is presented. The design is based on the combination of an enzyme-driven phosphorescence lifetime-based glucose-sensing assay and a thermoresponsive membrane anticipated to reduce biofouling. The metalloporphyrin, Pd meso-tetra(sulfophenyl)-tetrabenzoporphyrin ([PdPh4 (SO3 Na)4 TBP]3 , HULK) as well as glucose oxidase (GOx) are successfully incorporated into the UV-cured double network (DN) membranes by leveraging electrostatic interactions and covalent conjugation, respectively. The oxygen-sensitive metalloporphyrin is incorporated at different levels within the DN membranes. These HULK-containing membranes retain the desired thermosensitivity, as well as glucose diffusivity and primary optical properties of the metalloporphyrin. After subsequently modifying the membranes with GOx, glucose-sensing experiments reveal that membranes prepared with the lowest GOx level exhibit the expected increase in phosphorescent lifetime for glucose concentrations up to 200 mg dL-1 . For membranes prepared with relatively higher GOx, oxygen-limited behavior is considered the source of diminished sensitivity at higher glucose levels. This proof-of-concept study demonstrates the promising potential of a biosensor design integrating a specific optical biosensing chemistry into a thermoresponsive hydrogel membrane.

Comparative evaluation of mesenchymal stromal cell growth and osteogenic differentiation on a shape memory polymer scaffold.

Trauma-induced, critical-size bone defects pose a clinical challenge to heal. Albeit autografts are the standard-of-care, they are limited by their inability to be shaped to various defect geometries and often incur donor site complications. Herein, the combination of a "self-fitting" shape memory polymer (SMP) scaffold and seeded mesenchymal stromal cells (MSCs) was investigated as an alternative. The porous SMP scaffold, prepared from poly(ε-caprolactone) diacrylate (PCL-DA) and coated with polydopamine, provided conformal shaping and cell adhesion. MSCs from five tissues, amniotic (AMSCs), chorionic tissue (CHSCs), umbilical cord (UCSCs), adipose (ADSCs), and bone marrow (BMSCs) were evaluated for viability, density, and osteogenic differentiation on the SMP scaffold. BMSCs exhibited the fastest increase in cell density by day 3, but after day 10, CHSCs, UCSCs, and ADSCs approached similar cell density. BMSCs also showed the greatest calcification among the cell types, followed closely by ADSCs, CHSCs and AMSCs. Alkaline phosphatase (ALP) activity peaked at day 7 for AMSCs, UCSCs, ADSCs and BMSCs, and at day 14 for CHSCs, which had the greatest overall ALP activity. Of all the cell types, only scaffolds cultured with ADSCs in osteogenic media had increased hardness and local modulus as compared to blank scaffolds after 21 days of cell culture and osteogenic differentiation. Overall, ADSCs performed most favorably on the SMP scaffold. The SMP scaffold was able to support key cellular behaviors of MSCs and could potentially be a viable, regenerative alternative to autograft.

Amphiphilic silicones to mitigate lens epithelial cell growth on intraocular lenses.

Silicone intraocular lenses (IOLs) that resist lens epithelial cell (LEC) growth would greatly improve patient outcomes. Herein, amphiphilic surface modifying additives (SMAs) were incorporated into an IOL-type diphenyl silicone to reduce LEC growth without compromising opto-mechanical properties. The SMAs were poly(ethylene oxide)-silane amphiphiles (PEO-SAs) [H-Si-ODMSm-block-PEO8-OCH3], comprised of a PEO segment and siloxane tether of varying lengths (m = 0, 13, and 30). These three SMAs were each blended into the addition cure diphenyl silicone at varying concentrations (5, 10, 15, 20, and 25 µmol g-1) wherein the wt% of PEO was maintained for all SMAs at a given molar concentration. The chemical crosslinking and subsequent retention of SMAs in modified silicones was confirmed. Key material properties were assessed following equilibration in both air and aqueous environments. Silicones modified with SMAs having longer tethers (m = 13 and 30) underwent rapid and substantial water-driven restructuring of PEO to the surface to form highly hydrophilic surfaces, especially as SMA concentration increased. The % transmittance was also maintained for silicones modified with these particular SMAs. The moduli of the modified silicones were largely unchanged by the SMA and remained in the typical range for silicone IOLs. When the three SMAs were introduced at the highest concentration, modified silicones remained non-cytotoxic and LEC count and associated alpha-smooth muscle actin (α-SMA) expression decreased with increasing tether length. These results demonstrate the potential of silicones modified with PEO-SA SMAs to produce LEC-resistant IOLs.

Suitability of EtO Sterilization for Polydopamine-coated, Self-fitting Bone Scaffolds.

Irregularly shaped craniomaxillofacial (CMF) defects may be advantageously treated by "self-fitting" shape memory polymer (SMP) scaffolds, namely those prepared from poly(ε-caprolactone)diacrylate (PCL-DA) networks and PCL-DA/poly(L-lactic acid) (PLLA) (75:25 wt%) semi-interpenetrating polymer networks (semi-IPNs). In addition to achieving good scaffold-tissue contact, a polydopamine (PD) coating can be leveraged to enhance bioactivity for improved osseointegration. Sterilization with ethylene oxide (EtO) represents a logical choice due to its low operating temperature and humidity. Herein, for the first time, the impact of EtO sterilization on the material properties of PD-coated SMP scaffolds was systematically assessed. Morphological features (i.e., pore size and pore interconnectivity), and in vitro bioactivity were preserved as were PCL crystallinity, PLLA crystallinity, and crosslinking. These latter features led to sustained shape memory properties, and compressive modulus. EtO-sterilized, PD-coated scaffolds displayed similar in vitro degradation behaviors versus analogous non-sterilized scaffolds. This included maintenance of compression modulus following 28 days of exposure to non-accelerated degradation conditions.

Methodology for performing biomechanical push-out tests for evaluating the osseointegration of calvarial defect repair in small animal models.

Push-out tests are frequently used to evaluate the bone-implant interfacial strength of orthopedic implants, particularly dental and craniomaxillofacial applications. There currently is no standard method for performing push-out tests on calvarial models, leading to a variety of inconsistent approaches. In this study, fixtures and methods were developed to perform push-out tests in accordance with the following design objectives: (i) the system rigidly fixes the explanted calvarial sample, (ii) it minimizes lateral bending, (iii) it positions the defect accurately, and (iv) it permits verification of the coaxial alignment of the defect with the push-out rod. The fixture and method was first validated by completing push-out experiments on 30 explanted murine cranial caps and two explanted leporine cranial caps, all induced with bilateral sub-critical defects (5.0 mm and 8.0 mm nominal diameter for the murine and leporine models, respectively). Defects were treated with an autograft (i.e., excised tissue flap), a shape memory polymer (SMP) scaffold, or a PEEK implant. Additional validation was performed on 24 murine cranial caps induced with a single, unilateral critically-sized defect (8.0 mm nominal diameter) and treated with an autograft or a SMP scaffold.•A novel fixture was developed for performing push-out mechanical tests to characterize the strength of a bone-implant interface in calvarial defect repair.•The fixture uses a 3D printed vertical clamp with mating alignment component to fix the sample in place without inducing lateral bending and verify coaxial alignment of push-out rod with the defect.•The fixture can be scaled to different calvarial defect geometries as validated with 5.0 mm bilateral and 8.0 mm single diameter murine calvarial defect model and 8.0 mm bilateral leporine calvarial defect model.

Evaluation of a self-fitting, shape memory polymer scaffold in a rabbit calvarial defect model.

Self-fitting scaffolds prepared from biodegradable poly(ε-caprolactone)-diacrylate (PCL-DA) have been developed for the treatment of craniomaxillofacial (CMF) bone defects. As a thermoresponsive shape memory polymer (SMP), with the mere exposure to warm saline, these porous scaffolds achieve a conformal fit in defects. This behavior was expected to be advantageous to osseointegration and thus bone healing. Herein, for an initial assessment of their regenerative potential, a pilot in vivo study was performed using a rabbit calvarial defect model. Exogenous growth factors and cells were excluded from the scaffolds. Key scaffold material properties were confirmed to be maintained following gamma sterilization. To assess scaffold integration and neotissue infiltration along the defect perimeter, non-critically sized (d = 8 mm) bilateral calvarial defects were created in 12 New Zealand white rabbits. Bone formation was assessed at 4 and 16 weeks using histological analysis and micro-CT, comparing defects treated with an SMP scaffold (d = 9 mm x t = 1 or 2 mm) to untreated defects (i.e. defects able to heal without intervention). To further assess osseointegration, push-out tests were performed at 16 weeks and compared to defects treated with poly(ether ether ketone) (PEEK) discs (d = 8.5 mm x t = 2 mm). The results of this study confirmed that the SMP scaffolds were biocompatible and highly conducive to bone formation and ingrowth at the perimeter. Ultimately, this resulted in similar bone volume and surface area versus untreated defects and superior performance in push-out testing versus defects treated with PEEK discs. STATEMENT OF SIGNIFICANCE: Current treatments of craniomaxillofacial (CMF) bone defects include biologic and synthetic grafts but they are limited in their ability to form good contact with adjacent tissue. A regenerative engineering approach using a biologic-free scaffold able to achieve conformal fitting represents a potential "off-the-shelf" surgical product to heal CMF bone defects. Having not yet been evaluated in vivo, this study provided the preliminary assessment of the bone healing potential of self-fitting PCL scaffolds using a rabbit calvarial defect model. The study was designed to assess scaffold biocompatibility as well as bone formation and ingrowth using histology, micro-CT, and biomechanical push-out tests. The favorable results provide a basis to pursue establishing self-fitting scaffolds as a treatment option for CMF defects.

Smart scaffolds: shape memory polymers (SMPs) in tissue engineering.

Smart scaffolds based on shape memory polymer (SMPs) have been increasingly studied in tissue engineering. The unique shape actuating ability of SMP scaffolds has been utilized to improve delivery and/or tissue defect filling. In this regard, these scaffolds may be self-deploying, self-expanding, or self-fitting. Smart scaffolds are generally thermoresponsive or hydroresponsive wherein shape recovery is driven by an increase in temperature or by hydration, respectively. Most smart scaffolds have been directed towards regenerating bone, cartilage, and cardiovascular tissues. A vast variety of smart scaffolds can be prepared with properties targeted for a specific tissue application. This breadth of smart scaffolds stems from the variety of compositions employed as well as the numerous methods used to fabricated scaffolds with the desired morphology. Smart scaffold compositions span across several distinct classes of SMPs, affording further tunability of properties using numerous approaches. Specifically, these SMPs include those based on physically cross-linked and chemically cross-linked networks and include widely studied shape memory polyurethanes (SMPUs). Various additives, ranging from nanoparticles to biologicals, have also been included to impart unique functionality to smart scaffolds. Thus, given their unique functionality and breadth of tunable properties, smart scaffolds have tremendous potential in tissue engineering.

Intrinsic osteoinductivity of PCL-DA/PLLA semi-IPN shape memory polymer scaffolds.

Engineering osteoinductive, self-fitting scaffolds offers a potential treatment modality to repair irregularly shaped craniomaxillofacial bone defects. Recently, we innovated on osteoinductive poly(ε-caprolactone)-diacrylate (PCL-DA) shape memory polymers (SMPs) to incorporate poly-L-lactic acid (PLLA) into the PCL-DA network, forming a semi-interpenetrating network (semi-IPN). Scaffolds formed from these PCL-DA/PLLA semi-IPNs display stiffnesses within the range of trabecular bone and accelerated degradation relative to scaffolds formed from slowly degrading PCL-DA SMPs. Herein, we demonstrate for the first time that PCL-DA/PLLA semi-IPN SMP scaffolds show increased intrinsic osteoinductivity relative to PCL-DA. We also confirm that application of a bioinspired polydopamine (PD) coating further improves the osteoinductive capacity of these PCL-DA/PLLA semi-IPN SMPs. In the absence of osteogenic supplements, protein level assessment of human mesenchymal stem cells (h-MSCs) cultured in PCL-DA/PLLA scaffolds revealed an increase in expression of osteogenic markers osterix, bone morphogenetic protein-4 (BMP-4), and collagen 1 alpha 1 (COL1A1), relative to PCL-DA scaffolds and osteogenic medium controls. Likewise, the expression of runt-related transcription factor 2 (RUNX2) and BMP-4 was elevated in the presence of PD-coating. In contrast, the chondrogenic and adipogenic responses associated with the scaffolds matched or were reduced relative to osteogenic medium controls, indicating that the scaffolds display intrinsic osteoinductivity.