Primary left ventricular unloading with delayed reperfusion in patients with anterior ST-elevation myocardial infarction: Rationale and design of the STEMI-DTU randomized pivotal trial.

BACKGROUND: Despite successful primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI), myocardial salvage is often suboptimal, resulting in large infarct size and increased rates of heart failure and mortality. Unloading of the left ventricle (LV) before primary PCI may reduce infarct size and improve prognosis. STUDY DESIGN AND OBJECTIVES: STEMI-DTU (NCT03947619) is a prospective, randomized, multicenter trial designed to compare mechanical LV unloading with the Impella CP device for 30 minutes prior to primary PCI to primary PCI alone without LV unloading. The trial aims to enroll approximately 668 subjects, with a potential sample size adaptation, with anterior STEMI with a primary end point of infarct size as a percent of LV mass evaluated by cardiac magnetic resonance at 3-5 days after PCI. The key secondary efficacy end point is a hierarchical composite of the 1-year rates of cardiovascular mortality, cardiogenic shock ≥24 hours after PCI, use of a surgical left ventricular assist device or heart transplant, heart failure, intra-cardiac defibrillator or chronic resynchronization therapy placement, and infarct size at 3 to 5 days post-PCI. The key secondary safety end point is Impella CP-related major bleeding or major vascular complications within 30 days. Clinical follow-up is planned for 5 years. CONCLUSIONS: STEMI-DTU is a large-scale, prospective, randomized trial evaluating whether mechanical unloading of the LV by the Impella CP prior to primary PCI reduces infarct size and improves prognosis in patients with STEMI compared to primary PCI alone without LV unloading.

Microstructural control of modular peptide release from microporous biphasic calcium phosphate.

Drug release from tissue scaffolds is commonly controlled by using coatings and carriers, as well as by varying the binding affinity of molecules being released. This paper considers modulating synthetic peptide incorporation and release through the use of interconnected microporosity in biphasic calcium phosphate (BCP) and identifies the microstructural characteristics important to the release using experiments and a model of relative diffusivity. First, the release of three modular peptides designed to include an osteocalcin-inspired binding sequence based on bone morphogenic protein-2 (BMP-2) was compared and one was selected for further study. Next, the incorporation and release of the peptide from four types of substrates were compared: non-microporous (NMP) substrates had no microporosity; microporous (MP) substrates were either 50% microporous with 5µm pores (50/5), 60% microporous with 5µm pores (60/5), or 50% microporous with 50µm pores (50/50). Results showed that MP substrates incorporated significantly more peptide than NMP ones, but that the three different microporous substrates all incorporated the same total amount of peptide. NMP had a markedly lower release rate compared to each of three of the MP samples, though the initial burst release was the highest. The initial release and the release rate for the 60/5 samples were different from the 50/50, though they were not statistically different from the 50/5. The model indicated that the pore interconnection to pore size ratio, affecting the constriction between pores, had the greatest influence on the calculated relative diffusivity. While the model was consistent with the trends observed experimentally, the quantitative experimental results suggested that to attain an appreciable difference in release characteristics, both pore size and pore fraction should be changed for this system. These results contribute to rational scaffold design by showing that microstructure, specifically microporosity, can be used to modulate drug release.

Automated segmentation of micro-CT images of bone formation in calcium phosphate scaffolds.

In this work, we develop and validate an automated micro-computed tomography (micro-CT) image segmentation algorithm that accurately and efficiently segments bone, calcium phosphate (CaP)-based bone scaffold, and soft tissue. The algorithm enables quantitative evaluation of bone growth in CaP scaffolds in our study that includes many samples (100+) and large data sets (900 images per sample). The use of micro-CT for such applications is otherwise limited because the similarity in X-ray attenuation for the two materials makes them indistinguishable. Destructive characterization using histological techniques and scanning electron microscopy (SEM) has been the standard for CaP scaffolds, but these methods are cumbersome, inaccurate, and yield only 2D information. The proposed algorithm exploits scaffold periodicity and combines signal analysis, edge detection, and knowledge of three-dimensional spatial relationships between bone, CaP scaffold, and soft tissue to achieve fast and accurate segmentation. Application of this algorithm can lead to a new understanding of the role of CaP and scaffold internal structure on patterns and rates of bone growth.

Analysis of the roles of microporosity and BMP-2 on multiple measures of bone regeneration and healing in calcium phosphate scaffolds.

Osteoinductive agents, such as BMP-2, are known to improve bone formation when combined with scaffolds. Microporosity (<20 µm) has also been shown to influence bone regeneration in calcium phosphate (CaP) scaffolds. However, many studies use only the term "osteoconductive" to describe the effects of BMP-2 and microporosity on bone formation, and do not assess the degree of healing that occurred. The objective of this study was to quantify the influence of BMP-2 and microporosity on bone regeneration and healing in biphasic calcium phosphate scaffolds using multiple measures including bone volume fraction, radial distribution, and specific surface area. These measures were quantitatively compared by analyzing microcomputed tomography data and used to formally define and assess healing. A custom image segmentation program was used to segment >100 samples, with 900 images each, that were implanted in porcine mandibular defects for 3, 6, 12 and 24 weeks. The assessment of healing presented in this work demonstrates the level of detail possible in evaluating scaffold-guided bone regeneration. The analysis shows that BMP-2 and microporosity accelerate healing up to 4-fold. BMP-2 and microporosity were shown to have different and complementary roles in bone formation that effect the time needed for a defect to heal.

Multiscale osteointegration as a new paradigm for the design of calcium phosphate scaffolds for bone regeneration.

The role of macropore size (>100 microm) and geometry in synthetic scaffolds for bone regeneration has been studied extensively, but successful translation to the clinic has been slow. Significantly less attention has been given to porosity at the microscale (0.5-10 microm). While some have shown that microporosity in calcium phosphate (CaP)-based scaffolds can improve rate and extent of bone formation in macropores, none has explored microporosity as an additional and important space for bone ingrowth. Here we show osteointegration of biphasic calcium phosphate (BCP) scaffolds at both the macro and micro length scales. Bone, osteoid, and osteogenic cells fill micropores in scaffold rods and osteocytes are embedded in mineralized matrix in micropores, without the addition of growth factors. This work further highlights the importance of considering design parameters at the microscale and demonstrates the possibility for a bone-scaffold composite with no "dead space." Embedded osteocytes distributed throughout microporous rods may form a mechanosensory network, which would not be possible in scaffolds without microporosity. Multiscale osteointegration has the potential to greatly improve overall performance of these scaffolds through an improvement of mechanical properties, load transfer, and stability in the long and short term, and represents a new paradigm for scaffold design.

The effect of BMP-2 on micro- and macroscale osteointegration of biphasic calcium phosphate scaffolds with multiscale porosity.

It is well established that scaffolds for applications in bone tissue engineering require interconnected pores on the order of 100 microm for bone in growth and nutrient and waste transport. As a result, most studies have focused on scaffold macroporosity (>100 microm). More recently researchers have investigated the role of microporosity in calcium phosphate -based scaffolds. Osteointegration into macropores improves when scaffold rods or struts contain micropores, typically defined as pores less than approximately 50 microm. We recently demonstrated multiscale osteointegration, or growth into both macropores and intra-red micropores (<10 microm), of biphasic calcium phosphate (BCP) scaffolds. The combined effect of BMP-2, a potent osteoinductive growth factor, and multiscale porosity has yet to be investigated. In this study we implanted BCP scaffolds into porcine mandibular defects for 3, 6, 12 and 24 weeks and evaluated the effect of BMP-2 on multiscale osteointegration. The results showed that given this in vivo model BMP-2 influences osteointegration at the microscale, but not at the macroscale, but not at the macroscale. Cell density was higher in the rod micropores for scaffolds containing BMP-2 compared with controls at all time points, but BMP-2 was not required for bone formation in micropores. In contrast, there was essentially no difference in the fraction of bone in macropores for scaffolds with BMP-2 compared with controls. Additionally, bone in macropores seemed to have reached steady-state by 3 weeks. Multiscale osteointegration results in bone-scaffold composites that are fully osteointegrated, with no 'dead space'. These composites are likely to contain a continuous cell network as well as the potential for enhanced load transfer and improved mechanical properties.