Exercise-induced piezoelectric stimulation for cartilage regeneration in rabbits.

More than 32.5 million American adults suffer from osteoarthritis, and current treatments including pain medicines and anti-inflammatory drugs only alleviate symptoms but do not cure the disease. Here, we have demonstrated that a biodegradable piezoelectric poly(L-lactic acid) (PLLA) nanofiber scaffold under applied force or joint load could act as a battery-less electrical stimulator to promote chondrogenesis and cartilage regeneration. The PLLA scaffold under applied force or joint load generated a controllable piezoelectric charge, which promoted extracellular protein adsorption, facilitated cell migration or recruitment, induced endogenous TGF-ß via calcium signaling pathway, and improved chondrogenesis and cartilage regeneration both in vitro and in vivo. Rabbits with critical-sized osteochondral defects receiving the piezoelectric scaffold and exercise treatment experienced hyaline-cartilage regeneration and completely healed cartilage with abundant chondrocytes and type II collagen after 1 to 2 months of exercise (2 to 3 months after surgery including 1 month of recovery before exercise), whereas rabbits treated with nonpiezoelectric scaffold and exercise treatment had unfilled defect and limited healing. The approach of combining biodegradable piezoelectric tissue scaffolds with controlled mechanical activation (via physical exercise) may therefore be useful for the treatment of osteoarthritis and is potentially applicable to regenerating other injured tissues.

Access to liver transplantation for minority populations in the United States.

PURPOSE OF REVIEW: Racial disparities in access to liver transplantation have been known since the National Transplant Act of 1980. Since the inception of the Final Rule in 2000, the United Network of Organ Sharing has sought to ensure the equitable distribution of donor livers. Despite several measures aimed to improve access for vulnerable populations, disparities in outcomes are still prevalent throughout the liver transplant (LT) evaluation, while on the waitlist, and after liver transplantation. RECENT FINDINGS: Blacks and Hispanics are underrepresented on the LT list and have an increased waitlist mortality rate compared to Whites. Additionally, Blacks have a significantly higher risk of posttransplant mortality. SUMMARY: Ongoing efforts are necessary to eliminate inequities in transplant access. Strategies such as policy implementation and increasing diversity in the healthcare workforce may prove efficacious in creating change.

In Vivo Evaluation of the Regenerative Capability of Glycylglycine Ethyl Ester-Substituted Polyphosphazene and Poly(lactic-co-glycolic acid) Blends: A Rabbit Critical-Sized Bone Defect Model.

In an effort to understand the biological capability of polyphosphazene-based polymers, three-dimensional biomimetic bone scaffolds were fabricated using the blends of poly[(glycine ethylglycinato)75(phenylphenoxy)25]phosphazene (PNGEGPhPh) and poly(lactic-co-glycolic acid) (PLGA), and an in vivo evaluation was performed in a rabbit critical-sized bone defect model. The matrices constructed from PNGEGPhPh-PLGA blends were surgically implanted into 15 mm critical-sized radial defects of the rabbits as structural templates for bone tissue regeneration. PLGA, which is the most commonly used synthetic bone graft substitute, was used as a control in this study. Radiological and histological analyses demonstrated that PNGEGPhPh-PLGA blends exhibited favorable in vivo biocompatibility and osteoconductivity, as the newly designed matrices allowed new bone formation to occur without adverse immunoreactions. The X-ray images of the blends showed higher levels of radiodensity than that of the pristine PLGA, indicating higher rates of new bone formation and regeneration. Micro-computed tomography quantification revealed that new bone volume fractions were significantly higher for the PNGEGPhPh-PLGA blends than for the PLGA controls after 4 weeks. The new bone volume increased linearly with increasing time points, with the new tissues observed throughout the defect area for the blend and only at the implant site's extremes for the PLGA control. Histologically, the polyphosphazene system appeared to show tissue responses and bone ingrowths superior to PLGA. By the end of the study, the defects with PNGEGPhPh-PLGA scaffolds exhibited evidence of effective bone tissue ingrowth and minimal inflammatory responses. Thus, polyphosphazene-containing biomaterials have excellent translational potential for use in bone regenerative engineering applications.

Excess Deaths Among Blacks and Latinx Compared to Whites During Covid-19.

IMPORTANCE: Blacks and Latinx are disproportionately affected by Coronavirus disease 2019 (Covid-19) and experience higher mortality rates than Whites and Asians in the USA. Such racial disparities, in Covid-19 testing, cases, and mortality are visible in Connecticut too. Recently, excess deaths have become an important consideration in news reports and academic research. However, data on racial differences in excess death is limited. OBJECTIVE: This study examines racial/ethnic differences in excess deaths in the state of Connecticut during the Covid-19 pandemic. DESIGN: This is a cross-sectional epidemiological study to estimate excess deaths by racial/ethnic status utilizing mortality data during the peak months of Covid-19 infections from March 1 to June 30, 2020, in Connecticut. The following assumption is applied: expected non-Covid-19 deaths from March 1 to June 30, 2020, are equal to the number of deaths occurring during the period of March 1 to June 30, 2019. Race/ethnicity are defined as Non-Hispanic White, Non-Hispanic Black, and Latinx. Descriptive statistics and rates with 95% confidence intervals are presented. Chi-square analyses are performed where applicable. SETTING: Connecticut PARTICIPANTS: All deaths in Connecticut from March 1 to June 30, 2020. EXPOSURE: Covid-19 and race/ethnicity RESULTS: From March 1 to June 30, 2020, a total of 14,226 all-cause deaths occurred including 1514 Blacks (10.6%), 1095 Latinx (7.7%), and 11,617 Whites (81.7%). This represented a 74% increase in mortality for Blacks; 63% for Latinx, and 30% for Whites. In addition, 42.70% of the deaths in Blacks were attributed to Covid-19; 38.5% for Latinx, and 23.0% for Whites (p<0.001). Covid-19 deaths accounted for over 90% of the excess deaths in Blacks and Hispanics. In contrast, in Whites, Covid-19 deaths exceeded the number of excess deaths by 353 cases (113.2%), indicating that some Whites may have died from other underlined health conditions with a positive Covid-19 diagnosis. Furthermore, there was an increase in undetermined deaths in 2020, which accounted for 10.8% of deaths in Blacks, 13% in Latinx, and 6.2% of deaths in Whites. CONCLUSIONS AND RELEVANCE: Excess deaths in Blacks and Latinx were found above the numbers of deaths determined to have occurred due to Covid-19. The fact that a large number of undetermined deaths were found for Blacks and Latinx individuals, and testing rates for Blacks and Latinx individuals (as determined by positivity rates) were lacking during this period strongly suggests, these excess deaths were Covid-19-related deaths. The study findings indicate that Black and Latinx COVID-19-related deaths may be underreported in this pandemic. We advocate for targeted strategies that increase testing capacity, treatment, and vaccine availability in Black and Latinx communities.

Regenerative Cell-Based Therapies: Cutting Edge, Bleeding Edge, and Off the Edge.

With the emergence of cell-based therapies as viable treatment options readily accessible to patients, the scientific community and public have raised concerns regarding consumer accessibility and regulation enforcement. Opposing viewpoints regarding regulation have emerged, and efforts to maintain the balance between promoting scientific innovation and ensuring public safety has proved challenging. To further complicate matters, there is contradictory information regarding the clinical safety and efficacy of cell-based treatments. Herein, we outline the FDA's regulatory framework for cell-based therapies and describe what we term the cutting edge, bleeding edge, and off the edge interventions. We conclude with a new classification system for regenerative cell-based therapies intended to further aid in delineating between the clinically and scientifically sound therapies to those that compel further scientific investigation.

Mechanically superior matrices promote osteointegration and regeneration of anterior cruciate ligament tissue in rabbits.

The gold standard treatment for anterior cruciate ligament (ACL) reconstruction is the use of tendon autografts and allografts. Limiting factors for this treatment include donor site morbidity, potential disease transmission, and variable graft quality. To address these limitations, we previously developed an off-the-shelf alternative, a poly(l-lactic) acid (PLLA) bioengineered ACL matrix, and demonstrated its feasibility to regenerate ACL tissue. This study aims to 1) accelerate the rate of regeneration using the bioengineered ACL matrix by supplementation with bone marrow aspirate concentrate (BMAC) and growth factors (BMP-2, FGF-2, and FGF-8) and 2) increase matrix strength retention. Histological evaluation showed robust tissue regeneration in all groups. The presence of cuboidal cells reminiscent of ACL fibroblasts and chondrocytes surrounded by an extracellular matrix rich in anionic macromolecules was up-regulated in the BMAC group. This was not observed in previous studies and is indicative of enhanced regeneration. Additionally, intraarticular treatment with FGF-2 and FGF-8 was found to suppress joint inflammation. To increase matrix strength retention, we incorporated nondegradable fibers, polyethylene terephthalate (PET), into the PLLA bioengineered ACL matrix to fabricate a "tiger graft." The tiger graft demonstrated the greatest peak loads among the experimental groups and the highest to date in a rabbit model. Moreover, the tiger graft showed superior osteointegration, making it an ideal bioengineered ACL matrix. The results of this study illustrate the beneficial effect bioactive factors and PET incorporation have on ACL regeneration and signal a promising step toward the clinical translation of a functional bioengineered ACL matrix.

Just in TIME: Trauma-Informed Medical Education.

Numerous organizations implement a trauma-informed approach. This model assists institutions in providing care and education that delivers support to members who have undergone traumatic experiences, and many institutions apply the principles as a universal precaution. Student and trainee experiences in medical education reveal a hidden curriculum that may deliver conflicting messages about the values of an institution, in which equity is promoted, but biased and discriminatory practices are commonplace. Implicit racial bias has been identified in the patient-provider interaction and may also extend its impact on the learner experience. Bias and discrimination inflict trauma on its targets via emotional injury. Applying the principles of the trauma-informed approach, we advocate for trauma-informed medical education (TIME). TIME fosters awareness that students and trainees can experience trauma from a biased system and culture and advocates for the establishment of policies and practices that support learners to prevent further re-traumatization. TIME will serve as a means to deliver just and equitable education.

We Are the First to Applaud You Regarding Your Efforts in COVID-19: A Message from the African Diaspora to Our Brothers and Sisters of Africa.

As African countries address the COVID-19 pandemic, we applaud the continent and its efforts in the crisis, and offer a message that includes lessons learned from the American experience.

The COVID-19 Pandemic: a Call to Action to Identify and Address Racial and Ethnic Disparities.

The Coronavirus disease 2019 (COVID-19) pandemic has significantly impacted and devastated the world. As the infection spreads, the projected mortality and economic devastation are unprecedented. In particular, racial and ethnic minorities may be at a particular disadvantage as many already assume the status of a marginalized group. Black Americans have a long-standing history of disadvantage and are in a vulnerable position to experience the impact of this crisis and the myth of Black immunity to COVID-19 is detrimental to promoting and maintaining preventative measures. We are the first to present the earliest available data in the peer-reviewed literature on the racial and ethnic distribution of COVID-19-confirmed cases and fatalities in the state of Connecticut. We also seek to explode the myth of Black immunity to the virus. Finally, we call for a National Commission on COVID-19 Racial and Ethnic Health Disparities to further explore and respond to the unique challenges that the crisis presents for Black and Brown communities.

Nail matrix regenerative engineering: in vitro evaluation of poly(lactide-co-glycolide)/gelatin fibrous substrates.

Acute traumatic nail injury treatment repair procedures are commonly conducted in emergency departments and primary care offices. Current repair methods use nail splints that are inserted within the nail root to prevent the fusion of the proximal nail fold and the matrix tissue. Splints provide a protective barrier overlying the nail bed soft tissue during recovery periods, but uncertain prognoses (i.e., aesthetic and functional disadvantages) reveal a need for improved nail repair techniques. Nail splints are not specifically designed for nail organ restoration via biological mechanisms, thus, a clinical application that utilizes regenerative engineering techniques can prove useful in improving the nail injury prognoses. Using the coaxial electrospinning method, hybrid poly(lactide-co-glycolide) (PLGA) (85:15) and gelatin fibrous scaffolds (Hybrid1: PLGA shell, gelatin core and Hybrid2 : gelatin shell, PLGA core) with average fiber diameters of 540 ± 118 and 2,215 ± 1,135 nm, respectively, were produced and successful encapsulation of core fibers was observed. Furthermore, nail stem cells expressing stem cell characteristic markers CD90, CD29, and Lgr6 showed preferred attachment to Hybrid2 scaffolds after 24 hr. Overall, an in vitro regenerative engineered nail matrix may aid to improve the cosmetic appearance and function of injured nail organs post-traumatic injury.

Progress in 3D bioprinting technology for tissue/organ regenerative engineering.

Escalating cases of organ shortage and donor scarcity worldwide are alarming reminders of the need for alternatives to allograft tissues. Within the last three decades, research efforts in the field of regenerative medicine and tissue engineering continue to address the unmet need for artificial tissues and organs for transplant. Work in the field has evolved to create what we consider a new field, Regenerative Engineering, defined as the Convergence of advanced materials science, stem cell science, physics, developmental biology and clinical translation towards the regeneration of complex tissues and organ systems. Included in the regenerative engineering paradigm is advanced manufacturing. Three-dimensional (3D) bioprinting is a promising and innovative biofabrication strategy to precisely position biologics, including living cells and extracellular matrix (ECM) components, in the prescribed 3D hierarchal organization to create artificial multi-cellular tissues/organs. In this review, we outline recent progress in several bioprinting technologies used to engineer scaffolds with requisite mechanical, structural, and biological complexity. We examine the process parameters affecting bioprinting and bioink-biomaterials and review notable studies on bioprinted skin, cardiac, bone, cartilage, liver, lung, neural, and pancreatic tissue. We also focus on other 3D bioprinting application areas including cancer research, drug testing, high-throughput screening (HTS), and organ-on-a-chip models. We also highlight the current challenges associated with the clinical translation of 3D bioprinting and conclude with the future perspective of bioprinting technology.

Medical Surprise Anticipation and Recognition Capability: A New Concept for Better Health Care.

Predicting and preparing for the unforeseen is challenging. Medicine and health care are continuously changing based on science, technology, and regulation. This very process of change creates pathways for surprise and leaves us vulnerable to its impact. The armed forces have established strategies to identify and address surprising events, a framework that can be adapted to benefit the medical community. We introduce Medical Surprise Anticipation and Recognition Capability (SARC), adapted from an established military strategy. SARC is the process of addressing surprising events before they emerge. We explore the framework for mitigating surprise as developed by the Committee on Capability Surprise on U.S. Naval Forces. We recommend further exploration of this concept in health care as a potential asset in our quest towards high reliability.

Cancer Survivors and the Patient-Centered Medical Home.

Survivor care plans have been described as useful tools for enhancing the quality of follow-up care that cancer survivors receive after their active treatment has been completed. The relative success of current survivor care plan models is strongly dependent on the actions of individual patients. In this qualitative study of 33 cancer survivors, we explored patients' understanding of follow-up care and their motivations and resources for seeking care. Three types of survivor experiences were identified from narratives of patients treated in community oncology and NCI designated comprehensive cancer centers, ranging from non-activated patients who need enhanced health care communication and decision support to navigate their care to highly activated patients adept at navigating complex health care settings. Using the Patient-Centered Medical Home as a conceptual framework, we propose a research, policy and practice agenda that advocates for multi-faceted decision support to enhance cancer survivorship and follow-up care.