Best practices for enhancing surgical research: a perspective from the Canadian Association of Chairs of Surgical Research

Summary: The Canadian Association of Chairs of Surgical Research was created in 2014, with representation from every departmental surgical research committee across Canada, to establish Canadian surgical research as a beacon for health care innovation and to propose solutions for the daily challenges facing surgeon-researchers. Our key mandate has been to identify challenges for surgeons and scientists performing research to prevent further erosion of this vital area of activity that benefits patients, health care service providers and Canadian society. This article outlines the findings of a nationwide survey sent to all members of departments of surgery across Canada, seeking input on current threats and potential solutions. The results suggest that surgical research in Canada is experiencing a decline in funding and an increase in challenges affecting research productivity of academic surgeons, such as pressures to be clinically active, unpredictable surgical schedules, growing administrative demands, and increasing complexity of patient populations. Although surgeons are productive in their research endeavours, institutional changes and sharing of best practices are needed to ensure sustainable growth of research programs.

Two-Dimensional Magnesium Phosphate Nanosheets Form Highly Thixotropic Gels That Up-Regulate Bone Formation.

Hydrogels composed of two-dimensional (2D) nanomaterials have become an important alternative to replace traditional inorganic scaffolds for tissue engineering. Here, we describe a novel nanocrystalline material with 2D morphology that was synthesized by tuning the crystallization of the sodium-magnesium-phosphate system. We discovered that the sodium ion can regulate the precipitation of magnesium phosphate by interacting with the crystal's surface causing a preferential crystal growth that results in 2D morphology. The 2D nanomaterial gave rise to a physical hydrogel that presented extreme thixotropy, injectability, biocompatibility, bioresorption, and long-term stability. The nanocrystalline material was characterized in vitro and in vivo and we discovered that it presented unique biological properties. Magnesium phosphate nanosheets accelerated bone healing and osseointegration by enhancing collagen formation, osteoblasts differentiation, and osteoclasts proliferation through up-regulation of COL1A1, RunX2, ALP, OCN, and OPN. In summary, the 2D magnesium phosphate nanosheets could bring a paradigm shift in the field of minimally invasive orthopedic and craniofacial interventions because it is the only material available that can be injected through high gauge needles into bone defects in order to accelerate bone healing and osseointegration.

Hypoxia signalling manipulation for bone regeneration.

Hypoxia-inducible factor (HIF) signalling is intricately involved in coupling angiogenesis and osteogenesis during bone development and repair. Activation of HIFs in response to a hypoxic bone micro-environment stimulates the transcription of multiple genes with effects on angiogenesis, precursor cell recruitment and differentiation. Substantial progress has been made in our understanding of the molecular mechanisms by which oxygen content regulates the levels and activity of HIFs. In particular, the discovery of the role of oxygen-dependent hydroxylase enzymes in modulating the activity of HIF-1α has sparked interest in potentially promising therapeutic strategies in multiple clinical fields and most recently bone healing. Several small molecules, termed hypoxia mimics, have been identified as activators of the HIF pathway and have demonstrated augmentation of both bone vascularity and bone regeneration in vivo. In this review we discuss key elements of the hypoxic signalling pathway and its role in bone regeneration. Current strategies for the manipulation of this pathway for enhancing bone repair are presented with an emphasis on recent pre-clinical in vivo investigations. These findings suggest promising approaches for the development of therapies to improve bone repair and tissue engineering strategies.

Electrocatalytic Oxygen Reduction Performance of Silver Nanoparticle Decorated Electrochemically Exfoliated Graphene.

We have developed a potentiostatic double-pulse technique for silver nanoparticle (Ag NP) deposition on graphene (GRn) with superior electronic and ionic conductivity. This approach yielded a two-dimensional electrocatalyst with a homogeneous Ag NP spatial distribution having remarkable performance in the oxygen reduction reaction (ORR). GRn sheets were reproducibly prepared by the electrochemical exfoliation of graphite (GRp) at high yield and purity with a low degree of oxidation. Polystyrenesulfonate added during exfoliation enhanced the stability of the GRn solution by preventing the restacking of the graphene sheets and increased its ionic conductivity. The potentiostatic double-pulse technique is generally used to electrodeposit Pt nanoparticles and remains challenging for silver metal that exhibits nucleation and growth potentials relatively close to each other. We judiciously exploited this narrow margin of potential, and for the first time we report Ag NP electrodeposited onto graphene with the subsequent ability to control both the density and the size of metallic nanoparticles. Considering the high activity along with the lower cost of Ag compared to Pt, these findings are highly relevant to the successful commercialization of fuel cells and other electrochemical energy devices.

Electropolymerized carbonic anhydrase immobilization for carbon dioxide capture.

Biomimetic carbonation carried out with carbonic anhydrase (CA) in CO2-absorbing solutions, such as methyldiethanolamine (MDEA), is one approach that has been developed to accelerate the capture of CO2. However, there are several practical issues, such as high cost and limited enzyme stability, that need to be overcome. In this study, the capacity of CA immobilization on a porous solid support was studied to improve the instability in the tertiary amine solvent. We have shown that a 63% porosity macroporous carbon foam support makes separation and reuse facile and allows for an efficient supply and presentation of CO2 to an aqueous solvent and the enzyme catalytic center. These enzymatic supports conserved 40% of their initial activity after 42 days at 70 °C in an amine solvent, whereas the free enzyme shows no activity after 1 h in the same conditions. In this work, we have overcome the technical barrier associated with the recovery of the biocatalyst after operation, and most of all, these electropolymerized enzymatic supports have shown a remarkable increase of thermal stability in an amine-based CO2 sequestration solvent.

Amorphous multimetal based catalyst for oxygen evolution reaction.

The development of efficient, low-cost water splitting electrocatalysts is needed to store energy by generating sustainable hydrogen from low power clean but intermittent energy sources such as solar and wind. Here, we report a highly sustained low overpotential for oxygen evolution reached by the unique combination of three metals (NiCoV) prepared from a simple low temperature auto-combustion process. The amorphous multimetal oxygen evolving catalyst could be stably coated on a stainless-steel support using a tribochemical particle blasting method to create an oxygen evolution reaction (OER) electrode with a low overpotential of 230 mV at 10 mA cm-2 and a low Tafel slope of 40 mV dec-1. In addition to their low overpotential, this oxygen evolving electrocatalyst preserved performance demonstrating a stability after 10 h at the technologically relevant current density and without any surface morphology alteration. Given the importance of sustainable hydrogen production, the development of this new OER catalyst points the way to removing a key technical bottleneck for the water splitting reaction and could offer a route to cost reduction and lowering hurdles to more widespread adaptation of electrolyser technologies for hydrogen production. Supplementary Information: The online version contains supplementary material available at 10.1007/s43939-024-00087-5.

Development of Neovasculature in Axially Vascularized Calcium Phosphate Cement Scaffolds.

Augmenting the vascular supply to generate new tissues, a crucial aspect in regenerative medicine, has been challenging. Recently, our group showed that calcium phosphate can induce the formation of a functional neo-angiosome without the need for microsurgical arterial anastomosis. This was a preclinical proof of concept for biomaterial-induced luminal sprouting of large-diameter vessels. In this study, we investigated if sprouting was a general response to surgical injury or placement of an inorganic construct around the vessel. Cylindrical biocement scaffolds of differing chemistries were placed around the femoral vein. A contrast agent was used to visualize vessel ingrowth into the scaffolds. Cell populations in the scaffold were mapped using immunohistochemistry. Calcium phosphate scaffolds induced 2.7-3 times greater volume of blood vessels than calcium sulphate or magnesium phosphate scaffolds. Macrophage and vSMC populations were identified that changed spatially and temporally within the scaffold during implantation. NLRP3 inflammasome activation peaked at weeks 2 and 4 and then declined; however, IL-1ß expression was sustained over the course of the experiment. IL-8, a promoter of angiogenesis, was also detected, and together, these responses suggest a role of sterile inflammation. Unexpectedly, the effect was distinct from an injury response as a result of surgical placement and also was not simply a foreign body reaction as a result of placing a rigid bioceramic next to a vein, since, while the materials tested had similar microstructures, only the calcium phosphates tested elicited an angiogenic response. This finding then reveals a potential path towards a new strategy for creating better pro-regenerative biomaterials.

Necrosis reduction efficacy of subdermal biomaterial mediated oxygen delivery in ischemic skin flaps.

Inadequate tissue blood supply as may be found in a wound or a poorly vascularised graft, can result in tissue ischemia and necrosis. As revascularization is a slow process relative to the proliferation of bacteria and the onset of tissue necrosis, extensive tissue damage and loss can occur before healing is underway. Necrosis can develop rapidly, and treatment options are limited such that loss of tissue following necrosis onset is considered unavoidable and irreversible. Oxygen delivery from biomaterials exploiting aqueous decomposition of peroxy-compounds has shown some potential in overcoming the supply limitations by creating oxygen concentration gradients higher than can be attained physiologically or by air saturated solutions. We sought to test whether subdermal oxygen delivery from a material composite that was buffered and contained a catalyst, to reduce hydrogen peroxide release, could ameliorate necrosis in a 9 × 2 cm flap in a rat model that reliably underwent 40 % necrosis if untreated. Blood flow in this flap reduced from near normal to essentially zero, along its 9 cm length and subdermal perforator vessel anastomosis was physically prevented by placement of a polymer sheet. In the middle, low blood flow region of the flap, treatment significantly reduced necrosis based on measurements from photographs and histological micrographs. No change was observed in blood vessel density but significant differences in HIF1-α, inducible nitric oxide synthase and liver arginase were observed with oxygen delivery.

Mollusk glue inspired mucoadhesives for biomedical applications.

Chitosan (CH), partially N-deacetylated chitin, is a biodegradable and biocompatible polymer that has shown great potential in drug delivery and tissue engineering applications. Although bioadhesive, CH has limited mucoadhesion in wet conditions due to weak interactions with biological surfaces. DOPA (3,4-dihydroxy-L-phenylalanine), a catechol-containing molecule naturally present in marine mussel foot proteins, has been shown to increase the mucoadhesion of several polymers. We report here a simple and bioinspired approach to enhance CH mucoadhesion in wet conditions by preparing mixed hydrogels including CH and different catechol-containing compounds, namely DOPA, hydrocaffeic acid (HCA), and dopamine (DA). We characterized the hydrogels for their swelling, release kinetics of the catechol compounds, and mucoadhesive strength to rabbit small intestine. The swelling of the hydrogels was pH dependent with maximum swelling at pH 1. The hydrogel swelling was higher in the presence of the DOPA and DA but lower in the presence of HCA. HCA/CH hydrogel also showed the slowest catechol release, most likely due to electrostatic interactions between CH and HCA. Lower hydrogel swelling and slower HCA release resulted in increased mucoadhesion: HCA/CH showed more than 2-fold enhancement of mucoadhesion to rabbit small intestine compared to CH alone. Since it is known that catechol compounds can be oxidized, we analyzed the oxidation of DOPA, HCA, and DA at different pH values and its effect on mucoadhesion. We found that oxidation occurring before contact with the intestinal mucosa did not improve mucoadhesion, while oxidation occurring during the contact further increased the mucoadhesion of HCA/CH hydrogels. These results show that mucoadhesion of CH hydrogels can be increased with a simple bioinspired approach, which has the potential to be applied to other polymers since it does not require any chemical modification.

Low temperature fabrication of spherical brushite granules by cement paste emulsion.

Secondary protonated calcium phosphates such as brushite (CaHPO(4)·2H(2)O) or monetite (CaHPO(4)) have a higher resorption potential in bone defects than sintered ceramics, e.g. tricalcium phosphate or hydroxyapatite. However, processing of these phosphates to monolithic blocks or granules is not possible by sintering due to thermal decomposition of protonated phosphates at higher temperatures. In this study a low temperature technique for the preparation of spherical brushite granules in a cement setting reaction is presented. These granules were synthesized by dispersing a calcium phosphate cement paste composed of ß-tricalcium phosphate and monocalcium phosphate together with a surfactant to an oil/water emulsion. The reaction products were characterized regarding their size distribution, morphology, and phase composition. Clinically relevant granule sizes ranging from 200 µm to 1 mm were obtained, whereas generally smaller granules were received with higher oil viscosity, increasing temperature or higher powder to liquid ratios of the cement paste. The hardened granules were microporous with a specific surface area of 0.7 m(2)/g and consisted of plate-like brushite (>95 % according to XRD) crystals of 0.5-7 µm size. Furthermore it was shown that the granules may be also used for drug delivery applications. This was demonstrated by adsorption of vancomycin from an aqueous solution, where a load of 1.45-1.88 mg drug per g granules and an almost complete release within 2 h was obtained.

Aqueous decomposition behavior of solid peroxides: Effect of pH and buffer composition on oxygen and hydrogen peroxide formation.

The ability of solid peroxides to provide sustained release of both oxygen and hydrogen peroxide makes them potentially suitable for oxygen release or antibacterial applications. Most recent reports using solid peroxides to augment oxygen levels do so by compounding solid peroxide powders in polymers to retard the aqueous decomposition. Compounds with peroxidase activity may be added to reduce hydrogen peroxide toxicity. Peroxides are rarely pure and are mixed with oxide and themselves decompose to form hydroxides in water. Therefore, even if buffering strategies are used, locally the pH at the surface of aqueously immersed peroxide particles is inevitably alkaline. Since pH affects the decomposition of peroxides and hydrogen peroxide stability, this study compared for the first-time the aqueous decomposition products of hydrogen and inorganic peroxides that are in use or have been used for medical applications of have been evaluated preclinically; calcium peroxide (CaO2), magnesium peroxide (MgO2), zinc peroxide (ZnO2), sodium percarbonate (Na2CO3.1.5H2O2) and hydrogen peroxide (H2O2). Since plasma can be approximated to be carbonate buffered phosphate solution, we maintained pH using carbonate and phosphate buffers and compared results with citrate buffers. For a given peroxide compound, we identified not only a strong effect of pH but also of buffer composition on the extent to which oxygen and hydrogen peroxide formation occurred. The influence of buffer composition was not previously appreciated, thereby establishing in vitro parameters for better design of intentional release of specific decomposition species. STATEMENT OF SIGNIFICANCE: This paper compares for the first time the aqueous decomposition products oxygen and hydrogen peroxide of solid peroxy compounds of metal cations, (calcium, magnesium, sodium and zinc) across a pH range that could feasibly be found in the body, (pH 5,7, 9) either physiologically or pathologically. We find that in addition to pH, buffer composition is also a critically important factor, making translation from in vitro models challenging. Cytotoxicity was related to hydrogen peroxide release, alkalinity and in the case of zinc peroxide to the cation itself. In vitro and preclinical studies generally report release data from polymer-peroxide composites and rarely compare peroxides with one another. Together our data provide guidance for oxygen and ROS delivery from these inorganic materials.

Self-assembled calcium pyrophosphate nanostructures for targeted molecular delivery.

Nanostructured, inorganic microspheres have many industrial applications, including catalysis, electronics, and particularly drug delivery, with several advantages over their organic counterparts. However, many current production methods require high energy input, use of harmful chemicals, and extensive processing. Here, the self-assembly of calcium pyrophosphate into nanofibre microspheres is reported. This process takes place at ambient temperature, with no energy input, and only salt water as a by-product. The formation of these materials is examined, as is the formation of nanotubes when the system is agitated, from initial precipitate to crystallisation. A mechanism of formation is proposed, whereby the nanofibre intermediates are formed as the system moves from kinetically favoured spheres to thermodynamically stable plates, with a corresponding increase in aspect ratio. The functionality of the nanofibre microspheres as targeted enteric drug delivery vehicles is then demonstrated in vitro and in vivo, showing that the microspheres can pass through the stomach while protecting the activity of a model protein, then release their payload in intestinal conditions.

Vertical bone augmentation with 3D-synthetic monetite blocks in the rabbit calvaria.

INTRODUCTION: Long-term success of osteointegrated dental implants requires sufficient volume of healthy bone at the recipient sites. However, this is frequently lacking as a result of trauma, tooth loss, or infection. Onlay autografting is amongst the most predictable techniques for craniofacial vertical bone augmentation, however, complications related to donor site morbidity are common and alternatives to onlay autografts are desirable. AIM: To develop and evaluate a new synthetic onlay block for vertical bone augmentation. MATERIAL AND METHODS: Sixteen synthetic monetite monolithic discs-shaped blocks were prepared using a 3D-printing technique. The blocks were computer-designed, and had a diameter of 9.0 mm, a thickness of either 4.0 mm (n = 8) or 3.0 mm (n = 8) and one 0.5-mm wide central hole that enabled their surgical fixation with osteosynthesis screws. The blocks were randomly allocated to each side of the calvaria (right or left) of eight New Zealand rabbits and fixed with screws to achieve vertical bone augmentation. Eight weeks after the surgical intervention, the animals were sacrificed and the calvaria were retrieved for histological analysis. The following parameters were analysed: the interaction between the graft and the original bone surface, the amount of bone ingrowth within the graft and the gain in bone height achieved by the procedure. Wilcoxon t-test was used to evaluate significant differences between the two types of monetite bone block grafts. RESULTS: The blocks were easy to handle and no damage or fracture was registered while being screw-fixated to the calvarial bone. As a result, the surgical procedure was easy and quick. After a healing of 8 weeks, the synthetic blocks were strongly fused to the calvarial bone surface. Upon histological observation, the monetite blocks appeared to be infiltrated by newly formed bone, without histological signs of necrosis, osteolysis or foreign body reaction. Histomorphometry revealed that bone augmentation occurred within and over the monetite block. The 4.0- and 3.0-mm high blocks were filled with newly formed bone with 35% and 41% of their respective volumes. These observations indicated that craniofacial bone augmentations of at least 4 mm could be achieved with synthetic monetite blocks. CONCLUSION: Within the limits of our study, this novel material may be able to eliminate the need for autologous bone transplantation for the augmentation of large vertical bone defects.

Skeletal regeneration for segmental bone loss: Vascularised grafts, analogues and surrogates.

Massive segmental bone defects (SBD) are mostly treated by removing the fibula and transplanting it complete with blood supply. While revolutionary 50 years ago, this remains the standard treatment. This review considers different strategies to repair SBD and emerging potential replacements for this highly invasive procedure. Prior to the technical breakthrough of microsurgery, researchers in the 1960s and 1970s had begun to make considerable progress in developing non autologous routes to repairing SBD. While the breaktthrough of vascularised bone transplantation solved the immediate problem of a lack of reliable repair strategies, much of their prior work is still relevant today. We challenge the assumption that mimicry is necessary or likely to be successful and instead point to the utility of quite crude (from a materials technology perspective), approaches. Together there are quite compelling indications that the body can regenerate entire bone segments with few or no exogenous factors. This is important, as there is a limit to how expensive a bone repair can be and still be widely available to all patients since cost restraints within healthcare systems are not likely to diminish in the near future. STATEMENT OF SIGNIFICANCE: This review is significant because it is a multidisciplinary view of several surgeons and scientists as to what is driving improvement in segmental bone defect repair, why many approaches to date have not succeeded and why some quite basic approaches can be as effective as they are. While there are many reviews of the literature of grafting and bone repair the relative lack of substantial improvement and slow rate of progress in clinical translation is often overlooked and we seek to challenge the reader to consider the issue more broadly.

Three-dimensional mineralization of dense nanofibrillar collagen-bioglass hybrid scaffolds.

Scaffolds for bone tissue engineering must meet a number of requirements such as biocompatibility, osteoconductivity, osteoinductivity, biodegradability, and appropriate biomechanical properties. A combination of type I collagen and 45S5 Bioglass may meet these requirements, however, little has been demonstrated on the effect of Bioglass on the potential of the collagen nanofibrillar three-dimensional mineralization and its influence on the structural and mechanical properties of the scaffolds. In this work, rapidly fabricated dense collagen-Bioglass hybrid scaffolds were assessed for their potential for immediate implantation. Hybrid scaffolds were conditioned, in vitro, in simulated body fluid (SBF) for up to 14 days and assessed in terms of changes in structural, chemical, and mechanical properties. MicroCT and SEM analyses showed a homogeneous distribution of Bioglass particles in the as-made hybrids. Mineralization was detected at day 1 in SBF, while ATR-FTIR microscopy and XRD revealed the presence of hydroxyl-carbonated apatite on the surface and within the two hybrid scaffolds at days 7 and 14. FTIR and SEM confirmed that the triple helical structure and typical banding pattern of fibrillar collagen was maintained as a function of time in SBF. Principal component analysis executed on ATR-FTIR microscopy revealed that the mineralization extent was a function of both Bioglass content and conditioning time in SBF. Tensile mechanical analysis showed an increase in the elastic modulus and a corresponding decrease in strain at ultimate tensile strength (UTS) as imparted by mineralization of scaffolds as a function of time in SBF and Bioglass content. Change in UTS was affected by Bioglass content. These results suggested the achievement of a hybrid matrix potentially suitable for bone tissue engineering.

Dispersion modeling in pore networks: A comparison of common pore-scale models and alternative approaches.

Mass transfer in porous media resulting from dispersion occurs in a wide variety of applications such as water treatment, flow batteries, flow in aquifers, enhanced oil recovery, and packed-bed reactors. The underlying mechanisms of dispersion are the molecular diffusion superimposed on the advective transport induced by the fluid flow. Modeling dispersion in pore networks can be performed at a much lower computational cost compared to that in direct numerical simulations (DNS) such as finite element or the lattice Boltzmann methods, so it can be regarded as a suitable alternative provided its accuracy is sufficient. The most common approach to model dispersion in network models is based on the first-order upwind scheme, despite its known limitations in terms of accuracy for certain flow and transport regimes. In this study, three alternative pore-scale models for dispersion, which are more accurate than the existing ones, were derived and tested in pore network simulations. These models were adopted from the CFD literature and are based on a spatial discretization of the advection-diffusion equation using the hybrid and power-law finite difference schemes and the exact solution of the one-dimensional advection-diffusion equation. Finally, considering dispersion problems over arbitrary porous structures, consisting of stick-and-ball geometries, and different flow and mass transfer arrangements, the developed models were validated. Validation was carried-out through comparisons between results obtained with DNS, using a finite element solver, and those from pore network simulations. It is shown that under a wide range of dispersion regimes (up to the onset of the dispersion power-law regime), the relative error (with respect to DNS results) introduced by the power-law and exact solution-based models is consistently below 1%, whereas the use of the upwind scheme leads to >10% of relative error, depending on the dispersion regime. All the dispersion models developed in this study were implemented as part of the open-source network modeling package, OpenPNM.

Effects of Oxygen and Glucose on Bone Marrow Mesenchymal Stem Cell Culture.

This study determines whether the viability of mesenchymal stem cell (MSC) in vitro is most sensitive to oxygen supply, energetic substrate supply, or accumulation of lactate. Mouse unmodified (wild type (WT)) and erythropoietin (EPO) gene-modified MSC is cultured for 7 days in normoxic (21%) and anoxic conditions. WT-MSC is cultured in anoxia for 45 days in high and regular glucose media and both have similar viability when compared to their normoxic controls at 7 days. Protein production of EPO-MSC is unaffected by the absence of oxygen. MSC doubling time and post-anoxic exposure is increased (WT: 32.3-73.3 h; EPO: 27.2-115 h). High glucose leads to a 37% increase in cell viability at 13 days and 17% at 30 days, indicating that MSC anoxic survival is affected by supply of metabolic substrate. However, after 30 days, little difference in viability is found, and at 45 days, complete cell death occurs in both the conditions. This death cannot be attributed to lack of glucose or lactate levels. MSC stemness is retained for both osteogenic and adipogenic differentiations. The absence of oxygen increases the doubling time of MSC but does not affect their viability, protein production, or differentiation capacity.

Bioinorganics and Wound Healing.

Wound dressings and the healing enhancement (increasing healing speed and quality) are two components of wound care that lead to a proper healing. Wound care today consists mostly of providing an optimal environment by removing waste and necrotic tissues from a wound, preventing infections, and keeping the wounds adequately moist. This is however often not enough to re-establish the healing process in chronic wounds; with the local disruption of vascularization, the local environment is lacking oxygen, nutrients, and has a modified ionic and molecular concentration which limits the healing process. This disruption may affect cellular ionic pumps, energy production, chemotaxis, etc., and will affect the healing process. Biomaterials for wound healing range from simple absorbents to sophisticated bioactive delivery vehicles. Often placing a material in or on a wound can change multiple parameters such as pH, ionic concentration, and osmolarity, and it can be challenging to pinpoint key mechanism of action. This article reviews the literature of several inorganic ions and molecules and their potential effects on the different wound healing phases and their use in new wound dressings.

Treatment of Critical-Sized Calvarial Defects in Rats with Preimplanted Transplants.

The local environment and the defect features have made the skull one of the most difficult regions to repair. Finding alternative strategies to repair large cranial defects, thereby avoiding the current limitations of autograft or polymeric and ceramic prostheses constitute an unmet need. In this study, the regeneration of an 8 mm critical-sized calvarial defect treated by autograft or by a monetite scaffold directly placed in the defect or preimplanted (either cranial bone transplant or subcutaneous pocket) and then transplanted within the bone defect is compared. The data reveal that transplantation of preimplanted monetite transplant scaffolds greatly improves the skull vault closure compared to subcutaneously preimplanted or directly placed materials. Autografts, while clearly filling the defect volume with bone appear effective since bone volume inside the defect volume is obviously high, but are not well fused to the skull. The preimplantation site has a large influence on the regeneration of the defect. Transplantation of induced bone inside materials has the potential to reduce the need for autograft harvest without damaging the skeleton. This first demonstration indicates that cranial repair may be possible without recourse to bioactives or cultured cell therapies.

Material-Induced Venosome-Supported Bone Tubes.

The development of alternatives to vascular bone grafts, the current clinical standard for the surgical repair of large segmental bone defects still today represents an unmet medical need. The subcutaneous formation of transplantable bone has been successfully achieved in scaffolds axially perfused by an arteriovenous loop (AVL) and seeded with bone marrow stromal cells or loaded with inductive proteins. Although demonstrating clinical potential, AVL-based approaches involve complex microsurgical techniques and thus are not in widespread use. In this study, 3D-printed microporous bioceramics, loaded with autologous total bone marrow obtained by needle aspiration, are placed around and next to an unoperated femoral vein for 8 weeks to assess the effect of a central flow-through vein on bone formation from marrow in a subcutaneous site. A greater volume of new bone tissue is observed in scaffolds perfused by a central vein compared with the nonperfused negative control. These analyses are confirmed and supplemented by calcified and decalcified histology. This is highly significant as it indicates that transplantable vascularized bone can be grown using dispensable vein and marrow tissue only. This is the first report illustrating the capacity of an intrinsic vascularization by a single vein to support ectopic bone formation from untreated marrow.