Recent Patents on Regenerative Medicine - Volume 2, Issue 1, 2012

Collagens are a major constituent of the extracellular matrices of many biological tissues. Their structural and biological roles in animal tissues have inspired the development of regenerative therapies that incorporate collagen as a base material, thus providing a naturally recognisable surface for cell attachment and proliferation. In this review, recent collagen-related patents / patent applications are divided into three main areas: methods of collagen extraction / purification / synthesis (Area 1), methods of collagen molecular modification / processing (Area 2) and collagen scaffolds / implants (Area 3). Within Area 1, there are disclosures for methods of obtaining collagenous materials, including a method that uses urea to isolate collagen from collagen-containing natural fibres. Methods have also emerged to avoid the risk of cross-species infection including the extraction of collagen from marine sources and the synthesis of modular collagenlike peptides in bacterium models. Within Area 2, there are recently disclosed methods that can increase the resistance of collagen to degradation, including covalent / non-covalent crosslinking and a method of stabilising the collagen triple helix through O-methylation. Methods have also been recently disclosed to remove antigenic surface carbohydrate moieties and for processing collagen to induce fibril fusion. Within Area 3, there have been developments in the functional use of collagen in regenerative therapies, including a method to decellularise thick collagen-rich tissue extracts for use as a scaffold, a method to provide a support mesh for collagen scaffolds such that they hold their external shape on implantation and a method which allows the creation of composite scaffolds and multi-layer scaffolds for trans-tissue implants. In addition, two recent patents disclose the use of collagen injections for the treatment of synovial joints and intervertebral discs. The recent advances in the art represent a culmination of many years of progressive work on collagenous materials from many scientific fields; there now exists a plethora of techniques to obtain collagen, to modify its structure / properties and to implement the material into a functional embodiment for tissue regeneration.

The main living element of the human body is the skeletal muscle. It is composed of myofibres and satellite cells, the adult stem cells responsible for skeletal muscle regeneration. Increasing confirmation suggests that satellite cells represent a heterogeneous population of cells with regenerative capacity and plasticity. Recent publications indicate numerous new findings in satellite and stem cells, from their developmental life and role as the main self-renewing myogenic stem cell in the adult skeletal muscle to their loss during aging. The present review is focused on skeletal muscle stem cells, including their identification, self-renewal ability, heterogeneity, and multilineage differentiation capacity. Finally, we summarize the latest developments, clinical applications and patents in regenerative medicine utilizing skeletal muscle stem cells.

The ability of cancer cells to divide indefinitely whilst supporting tumor growth, metastasis and invasiveness resembles the behavior of stem cells. Here, we overview the role of Polycomb (PcG)-dependent epigenetic silencing mechanisms in stem cell biology and cancer, focusing on two major PcG components, Ezh2 and Bmi1. In a recent patent, stem cell PcG targets were shown to be more prone to cancer-specific promoter DNA methylation than non-targets, indicating that reversible PcG-mediated gene repression becomes replaced by permanent silencing. This epigenetic switching keeps the cell in a sustained state of self-renewal, predisposing it to tumorigenic transformation. These findings might provide the means of identifying the stem-cell epigenetic signatures associated with the origin of specific types of cancer. Based on the reversibility of epigenetic histone modifications, PcG proteins have become established targets in clinical practice for the treatment of a variety of cancers, notably treatments with histone deacetylase and methyltransferase inhibitors. A number of reports and patents highlight the potential of alternative approaches to targeting PcG for cancer therapy, including micro-RNA expression and the use of Hedgehog signaling pathway antagonists. The major shortcoming of current approaches is their lack of specificity. The identification of tumorigenic epigenetic alterations together with the development of inhibitors to target them promises to open the way toward personalized cancer treatment.

Multiple system atrophy (MSA) is a neurodegenerative disease in which oligodendrocytes and neurons in the central nervous system (CNS) are affected. MSA is characterized by abnormal α-synuclein inclusions in oligodendrocytes, which are diagnostic of MSA. Formation of α-synuclein inclusions may be the primary lesions that eventually compromise neuronal function and viability. But little is known about the cellular mechanisms by which oligodendrocytic α- synuclein inclusions cause neuronal degeneration in MSA. Transgenic mice in which human wild-type α-synuclein was overexpressed in oligodendrocytes were generated as animal models of MSA. Oligodendrocytic inclusions induced neuronal accumulation of α-synuclein and progressive neuronal degeneration in the mouse CNS. In mouse neurons, endogenous α-synuclein binds to β-III tubulin in microtubules to form insoluble protein complexes, leading to neuronal dysfunction. The findings with mouse models suggest three pathological processes to underlie neurodegeneration in MSA: increase in neuronal expression of α-synuclein by oligodendrocytic inclusions, induction of neuronal accumulation of insoluble protein complexes by binding of α-synuclein to β-III tubulin and disturbance of α-synuclein modulation by neuronal activity. A positive perspective on the therapeutic target for MSA has been recently proposed. The methods to inhibit α-synuclein accumulation and those disclosed in related recent patent applications are summarized in this review.

The establishment of the first culture of a human embryonic stem cell (hESC) line as immortal and capable of producing virtually every cell of a human body generated high expectations regarding their potential use in regenerative medicine and research applications. The achievement of generating immortal pluripotent cells from adult tissues further raised those expectations, by ideally eliminating ethical and safety concerns regarding the use of human embryonic stem cells. Patient-specific stem cells could be generated, and no human embryo would have been used. After first six years of producing induced pluripotent stem cell lines from somatic tissues, advancements have been made but much research still needs to be conducted in order to produce clinically relevant differentiated cells from induced pluripotent stem cells. The present review outlines the most recent inventions and basic research related to the clinical applications of human pluripotent stem cells. Its main objective is to contribute a concise compilation of the advances in the derivation, culture, directed differentiation and development of application processes of human pluripotent stem cells, in the development of their clinical applications to treat human disease. Registered patents and related bibliography reported mostly from past two years have been considered for inclusion, although basic literature has been included where needed to explain recent developments.

Finding a cure for every single disease has been the ultimate dream of mankind throughout history. To this end, generation after generation has witnessed innumerable attempts to rewrite and revise the “book of cures.” Despite the unfinished journey to find treatment for all known diseases, several universal agreements with regard to what constitute the most likely successful strategies have been reached. First, to develop a successful healing outcome, one needs to specifically target the agent(s) causing the disease. Second, the body needs to be freed of the source(s) of the disease. Third, the damaged body parts/tissues need to be replaced with healthy ones. In the framework outlined above, three disciplines in the field of biomedical science, namely, gene therapy, stem cell therapy, and cell reprogramming, appear as the leading strategies to fulfill these goals, as they possess all the desired elements for treating disease. This patents review describes the past and present status of these three disciplines with an emphasis on advances in the cardiovascular field for each discipline.

Bone grafting has come a very long way since a Dutch surgeon used pieces of a dog's skull to repair a soldier's cranium in the 17th Century. Current technology aims to deliver a scaffold that combines the unique osteogenic properties of ceramic biocomposite materials to make the best mimic of physiologic conditions. To do so, a scaffold must provide: i) A three-dimensional platform allowing for osteogenic cellular attachment and growth and vascular formation, ii) Structural integrity while the damaged tissue heals, and iii) Non-toxic integration, degradation or resorption into the host over an appropriate time. The combination of inorganic, ceramic materials with cells, polymers and growth factors has come very close to creating a bone graft capable of meeting each of these requirements. Recent patents describe new methods to forming an ideal osteogenic matrix for both large and small bone repair. Many new technologies have been introduced that are very potent in their ability to heal small bone wounds and induce new bone formation, such as porous calcium phosphate pastes and hydroxyapatite cements. However, there is still a lack of quality and proven materials for load bearing purposes. This is a reminder of how much there still is to improve upon and that we are still a long way from creating bone products that are identical to the natural product. Despite these shortcomings, ceramic biocomposties represent one of the most promising materials in the bone graft field and their development and improvement will surely lead to a more natural bone replacement.

The recent patents annotated in this section have been selected from various patent databases, and are relevant to the articles published in this journal issue. The patents are categorized in fast emerging areas of regenerative medicine e.g. stem cells, human embryonic stem, gene therapy, tissue engineering, regenerative biomolecules, use of biomaterials for treating disease and injury, and tissue/ organ regeneration related to regenerative medicine.