Recent Patents on Regenerative Medicine - Volume 1, Issue 2, 2011

Regenerative medicine is a powerful interdisciplinary tool that allows novel therapeutic approaches to be developed for diseases with no effective treatment, and its potential has been substantially enhanced by recent advances. We review the latest strategies, patented and/or under clinical trial, for the development of therapies based on the formation of new bone and cartilaginous tissue from stem cells to replace injured, diseased, or poorly-developed tissue. Mesenchymal stem cells are the most widely used cell types. Strategies generally involve the extraction of stem cells from the patient, their expansion in culture, their reprogramming and, finally, implantation in the patient of alreadydifferentiated cells along with the matrix they form or another matrix or artificial scaffolding. In order to guarantee treatment success, the biomaterial transferred to the patients must be adequately anchored and sufficiently biocompatible. Patented protocols for stem cell differentiation include: using different types of exogenous factors or of specific ligands against receptors associated with various signaling routes, inducing differentiation by physical methods, or stimulating differentiation of the patient's stem cell population in situ. The complex range of methods and protocols in the literature suggest that we are at the starting point of an emerging area that promises to deliver a new platform superior to other technologies currently considered to be at the vanguard.

Human embryonic stem cells (hESCs) are genetically stable with unlimited expansion ability and unrestricted plasticity, proffering a pluripotent reservoir for in vitro derivation of a large supply of disease-targeted human somatic cells that are restricted to the lineage in need of repair. There is a large healthcare need to develop hESC-based therapeutic solutions to provide optimal regeneration and reconstruction treatment options for the damaged or lost tissue or organ that have been lacking. In spite of controversy surrounding the ownership of hESCs, the number of patent applications related to hESCs is growing rapidly. This review gives an overview of different patent applications on technologies of derivation, maintenance, differentiation, and manipulation of hESCs for therapies. Many of the published patent applications have been based on previously established methods in the animal systems and multi-lineage inclination of pluripotent cells through spontaneous germ-layer differentiation. Innovative human stem cell technologies that are safe and effective for human tissue and organ regeneration in the clinical setting remain to be developed. Our overall view on the current patent situation of hESC technologies suggests a trend towards hESC patent filings on novel therapeutic strategies of direct control and modulation of hESC pluripotent fate, particularly in a 3-dimensional context, when deriving clinicallyrelevant lineages for regenerative therapies.

Scarring remains a large market with as yet no prescription medication to reduce or prevent scarring. Studies have indicated that early human fetuses can heal cutaneous wounds with perfect regeneration and a number of theories have been proposed for this regenerative phenotype. These theories and variations between fetal and adult wound healing have been studied and a number have been patented as future potential therapeutics to reduce or prevent scarring.

Red blood cells are, by far, the most abundant cells in the blood; they have a critical role providing the oxygen and carrying away carbon dioxide. Transfusions save lives but red blood cells supply is more and more difficult. Therefore the idea of mimicking in vitro the in vivo red blood cell production comes up. This review focuses on the latest patents which have explored the potential of ex vivo manufacturing of red blood cells from hematopoietic stem cells or pluripotent embryonic and/or adult stem cells, thanks to the use of specific media, pivotal cytokine cocktails, extra cellular matrices, hypoxia and/or bioreactors. However since none of the patents is GMP-compliant, or ensure a sufficient production rate or assess the functionality of the produced cells, many critical points remain to be investigated to produce in vitro on a large scale basis safe and functional red blood cells.

The most recent advances in biotechnology have transformed regenerative medicine from a mere promise to a therapeutic reality for a wide range of diseases. Gene therapy, understood as the introduction of nucleic acids within altered cells, is designed to improve or cure patients with a disease and is presented as an essential tool for the progress of this novel type of therapy. There are already controlled clinical trials on very different types of disease, applying new therapeutic approaches based on the utilization of genes to obtain stem cells. All of these investigations are generating spectacular developments and, in many cases, the inventions are being protected by patents due to the considerable interest of industry and their possible commercialization. Indeed, the development of different technologies aimed to generate induced pluripotent stem cells has been one of the most active areas in the patent production during the last year. We review the principles of gene therapy and describe in detail the different clinical trials and the diseases under investigation. We also outline the advances underlying the patents related to its application in regenerative medicine, the therapeutic interventions that have been carried out, and the limitations and shortcomings that remain to be overcome.

Hematopoietic stem cells (HSC) are being considered as one of the most potential regimens for regenerative therapy in various disease states and last several decades of research helped us to understand them better regarding the regenerative capabilities of HSC. HSC can be isolated from different sources such as peripheral blood, bone marrow and cord blood. Rigorous scientific investigations on cell surface marker, biology, niche and functionality determined that self-renewal and multi-lineage differentiation capability possessed by HSCs and easy accessibility made them one of the most used stem cells for clinical applications. This review focuses not only on the recent advancement of HSC in restoration of hematopoiesis in different immunological and hematological malignancies but also on the contribution of HSC to vasculogenesis and angiogenesis especially in ischemic conditions in various tissues. We have emphasized about the promise in use of the HSC in regenerative medicine in various preclinical and clinical set-up. Being the first adult stem cell in the history of regenerative medicine, basic biology of HSC is well documented. Several attempts have been made to manipulate the basic biology of HSCs to adjust efficient implementation of HSC in preclinical models. In order to increase the benefit of transplantation effect in clinical practice, large numbers of stem cells were required, which were made possible by expansion of HSC. Here, we discussed in detail the techniques used to manipulate HSC niche and modifications of external stimulating factors to achieve large number of transplantable HSCs. HSCs are also being used as a targeted vehicle for gene delivery discussed in detail. Finally, we have cited some of the important patents, which reflect the breadth of the advances in basic HSC biology, expansion technique, preclinical models and clinical transplantation.

The cornea is the clear front of the eye and it is covered by an epithelium which is renewed by stem cells located at its periphery, in a region known as the limbus. These so-named limbal stem cells can become deficient due to hereditary or acquired causes resulting in the painful and blinding disease of limbal stem cell deficiency. The treatment of limbal stem cell deficiency includes the transplantation of healthy limbal tissue or cultured limbal epithelial cells. This manuscript describes the patents involved in this field of regenerative medicine, including the most recent patents filed. The concepts, procedures and devices outlined in recent patent applications will be reviewed.

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.