Unlocking the full potential of rare disease drug development: exploring the not-for-profit sector's contributions to drug development and access.

This commentary provides a comprehensive overview of the challenges and opportunities in the field of drug development for rare diseases and especially of gene therapy products for ultra-rare diseases. It discusses the limited market size, reimbursement and scientific complexities that deter pharmaceutical investment in this field. Highlighting the pivotal role of charitable organizations like Fondazione Telethon, it showcases their efforts in funding research and ensuring access to innovative therapies.

Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial.

Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3 (ANGPTL3)-as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo.

Test-retest reliability of wireless inertial-sensor derived measurements of knee joint kinematics.

Advances in sensor technology have provided an opportunity to measure gait characteristics using body-worn inertial measurement units (IMUs). Whilst research investigating the validity of IMUs in reporting gait characteristics is extensive, research investigating the reliability of IMUs is limited. This study aimed to investigate the inter-session reliability of wireless IMU derived measures of gait (i.

An Automatic Foot and Shank IMU Synchronization Algorithm: Proof-of-concept.

When using wearable sensors for measurement and analysis of human performance, it is often necessary to integrate and synchronise data from separate sensor systems. This paper describes a synchronization technique between IMUs attached to the shanks and insoles attached at the feet and aims to solve the need to compute the ankle joint angle, which relies on synchronized sensor data. This will additionally enable concurrent analysis using gait kinematic and kinetic features.

Orthotopic Bone Formation by Streamlined Engineering and Devitalization of Human Hypertrophic Cartilage.

Most bones of the human body form and heal through endochondral ossification, whereby hypertrophic cartilage (HyC) is formed and subsequently remodeled into bone. We previously demonstrated that HyC can be engineered from human mesenchymal stromal cells (hMSC), and subsequently devitalized by apoptosis induction. The resulting extracellular matrix (ECM) tissue retained osteoinductive properties, leading to ectopic bone formation.

Effects of Interleukin-1β Inhibition on Incident Hip and Knee Replacement : Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear.

Objective: To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR).

VEGF Over-Expression by Engineered BMSC Accelerates Functional Perfusion, Improving Tissue Density and In-Growth in Clinical-Size Osteogenic Grafts.

The first choice for reconstruction of clinical-size bone defects consists of autologous bone flaps, which often lack the required mechanical strength and cause significant donor-site morbidity. We have previously developed biological substitutes in a rabbit model by combining bone tissue engineering and flap pre-fabrication. However, spontaneous vascularization was insufficient to ensure progenitor survival in the core of the constructs.

Assessment of Low-Grade Focal Cartilage Lesions in the Knee With Sodium MRI at 7 T: Reproducibility and Short-Term, 6-Month Follow-up Data.

Objectives: Several articles have investigated potential of sodium (Na) magnetic resonance imaging (MRI) for the in vivo evaluation of cartilage health, but so far no study tested its feasibility for the evaluation of focal cartilage lesions of grade 1 or 2 as defined by the International Cartilage Repair Society. The aims of this study were to evaluate the ability of Na-MRI to differentiate between early focal lesions and normal-appearing cartilage, to evaluate within-subject reproducibility of Na-MRI, and to monitor longitudinal changes in participants with low-grade, focal chondral lesions.

Materials And Methods: Thirteen participants (mean age, 50.

The comparison of the performance of 3 T and 7 T T mapping for untreated low-grade cartilage lesions.

Objective: To investigate T mapping as a possible marker for low-grade human articular cartilage lesions during a one-year follow-up, possible changes during the follow-up and compare the reliability and sensitivity of these measurements on high-field (3 T) and ultra-high-field (7 T) MRI scanners.

Design: Twenty-one patients with femoral, tibial and patellar cartilage defect in the knee joint participated in the study. The MRI protocol consisted of morphological, as well as three-dimensional triple-echo steady-state (3D-TESS) T mapping sequences with similar parameters at 3T and 7T.

Monocytes Seeded on Engineered Hypertrophic Cartilage Do Not Enhance Endochondral Ossification Capacity.

Engineered hypertrophic cartilage (HC) represents an attractive bone substitute material, capable to induce bone formation by endochondral ossification. Since bone formation by HC depends on factors released from the extracellular matrix, in this study, we hypothesized that HC seeding with monocytes committed to osteoclastogenesis could enhance its remodeling, improve chemotaxis of skeletal and vascular cells, and consequently enhance bone formation. This would be particularly relevant for devitalized HC, which currently exhibits only limited osteoinductivity.

Fat-Derived Stromal Vascular Fraction Cells Enhance the Bone-Forming Capacity of Devitalized Engineered Hypertrophic Cartilage Matrix.

Unlabelled: : Engineered and devitalized hypertrophic cartilage (HC) has been proposed as bone substitute material, potentially combining the features of osteoinductivity, resistance to hypoxia, capacity to attract blood vessels, and customization potential for specific indications. However, in comparison with vital tissues, devitalized HC grafts have reduced efficiency of bone formation and longer remodeling times. We tested the hypothesis that freshly harvested stromal vascular fraction (SVF) cells from human adipose tissue-which include mesenchymal, endothelial, and osteoclastic progenitors-enhance devitalized HC remodeling into bone tissue.

Thoracic Outlet Syndrome in the Overhead Athlete: A Report of 2 Cases of Subclavius Posticus Muscle.

Subclavius posticus muscle is a supernumerary anatomical variation of the subclavius muscle. The aim of this study was to show the possible contribution of the posticus muscle in the development of unilateral thoracic outlet syndrome (TOS) in overhead athletes, presenting hypertrophy of the dominant arm due to their sport activity. Reported here are 2 young overhead athletes complaining pain, paresthesia, weakness in the dominant upper limb, although presenting none of the main shoulder and neurological disorders.

Engineering Small-Scale and Scaffold-Based Bone Organs via Endochondral Ossification Using Adult Progenitor Cells.

Bone development, growth, and repair predominantly occur through the process of endochondral ossification, characterized by remodelling of cartilaginous templates. The same route efficiently supports engineering of bone marrow as a niche for hematopoietic stem cells (HSC). Here we describe a combined in vitro/in vivo system based on bone marrow-derived Mesenchymal Stem/Stromal Cells (MSC) that duplicates the hallmark cellular and molecular events of endochondral ossification during development.

Stem Cells for Bone Regeneration: From Cell-Based Therapies to Decellularised Engineered Extracellular Matrices.

Currently, autologous bone grafting represents the clinical gold standard in orthopaedic surgery. In certain cases, however, alternative techniques are required. The clinical utility of stem and stromal cells has been demonstrated for the repair and regeneration of craniomaxillofacial and long bone defects although clinical adoption of bone tissue engineering protocols has been very limited.

One-step surgery with multipotent stem cells and Hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years.

Purpose: The aim of this study is to prospectively evaluate the medium-term effectiveness and regenerative capability of autologous adult mesenchymal stem cells, harvested as bone marrow aspirate concentrate (BMAC), along with a hyaluronan-based scaffold (Hyalofast) in the treatment of ICRS grade 4 chondral lesions of the knee joint, in patients older than 45 years.

Methods: A study group of 20 patients with an age >45 years (mean 50.0 ± 4.

Cartilage Repair in the Inflamed Joint: Considerations for Biological Augmentation Toward Tissue Regeneration.

Cartilage repair/regeneration procedures (e.g., microfracture, autologous chondrocyte implantation [ACI]) typically result in a satisfactory outcome in selected patients.

Fresh osteochondral allografts in the knee: only a salvage procedure?

The role of fresh allogeneic osteochondral allograft transplantation (OCA) in the cartilage repair algorithm has been long debated and this procedure is primarily considered as a salvage procedure, to be used when other, simple, techniques have failed. Gracitelli et al. in a retrospective comparison of patients who received OCA as primary treatment or as a salvage procedure, demonstrates that the outcome of this procedure is minimally influenced by a previous failed treatment and that OCA represents an effective solution for both primary and revision surgery of chondral and osteochondral lesions of the knee.

Generation and characterization of osteochondral grafts with human nasal chondrocytes.

We investigated whether nasal chondrocytes (NC) can be used to generate composite constructs with properties necessary for the repair of osteochondral (OC) lesions, namely maturation, integration and capacity to recover from inflammatory burst. OC grafts were fabricated by combining engineered cartilage tissues (generated by culturing NC or articular chondrocytes - AC - onto Chondro-Gide® matrices) with devitalized spongiosa cylinders (Tutobone®). OC tissues were then exposed to IL-1β for three days and cultured for additional 2 weeks in the absence of IL-1β.

Osteoinductivity of engineered cartilaginous templates devitalized by inducible apoptosis.

The role of cell-free extracellular matrix (ECM) in triggering tissue and organ regeneration has gained increased recognition, yet current approaches are predominantly based on the use of ECM from fully developed native tissues at nonhomologous sites. We describe a strategy to generate customized ECM, designed to activate endogenous regenerative programs by recapitulating tissue-specific developmental processes. The paradigm was exemplified in the context of the skeletal system by testing the osteoinductive capacity of engineered and devitalized hypertrophic cartilage, which is the primordial template for the development of most bones.

Engineered decellularized matrices to instruct bone regeneration processes.

Despite the significant progress in the field of bone tissue engineering, cell-based products have not yet reached the stage of clinical adoption. This is due to the uncertain advantages from the standard-of-care, combined with challenging cost-and regulatory-related issues. Novel therapeutic approaches could be based on exploitation of the intrinsic regenerative capacity of bone tissue, provided the development of a deeper understanding of its healing mechanisms.

Adult human neural crest-derived cells for articular cartilage repair.

In embryonic models and stem cell systems, mesenchymal cells derived from the neuroectoderm can be distinguished from mesoderm-derived cells by their Hox-negative profile--a phenotype associated with enhanced capacity of tissue regeneration. We investigated whether developmental origin and Hox negativity correlated with self-renewal and environmental plasticity also in differentiated cells from adults. Using hyaline cartilage as a model, we showed that adult human neuroectoderm-derived nasal chondrocytes (NCs) can be constitutively distinguished from mesoderm-derived articular chondrocytes (ACs) by lack of expression of specific HOX genes, including HOXC4 and HOXD8.

The benefit of synthetic versus biological patch augmentation in the repair of posterosuperior massive rotator cuff tears: a 3-year follow-up study.

Background: Rotator cuff repair typically results in a satisfactory, although variable, clinical outcome. However, anatomic failure of the repaired tendon often occurs.

Hypothesis: Patch augmentation can improve the results of open rotator cuff repair by supporting the healing process, protecting the suture, and reducing friction in the subacromial space.