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Alternatives to knee replacement, stem cells and fibroblast growth factor – Video

Posted: March 16, 2013 at 10:47 am


Alternatives to knee replacement, stem cells and fibroblast growth factor
http://www.stemcellsarthritistreatment.com In our series on alternatives to knee replacement, I want to discuss more components of cartilage repair. In addit...

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Alternatives to knee replacement, stem cells and fibroblast growth factor - Video

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Knee replacement alternatives: cartilage repair with stem cells and insulin like growth factor – Video

Posted: March 14, 2013 at 6:42 pm


Knee replacement alternatives: cartilage repair with stem cells and insulin like growth factor
http://www.stemcellsarthritistreatment.com When it comes to alternatives to knee replacement surgery, regenerative medicine techniques aimed at repairing car...

By: Nathan Wei

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Knee replacement alternatives: cartilage repair with stem cells and insulin like growth factor - Video

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Alternatives to knee replacement… fibroblast growth factor as an aid to stem cell cartilage repair – Video

Posted: March 4, 2013 at 5:42 pm


Alternatives to knee replacement... fibroblast growth factor as an aid to stem cell cartilage repair
http://www.stemcellsarthritistreatment.com In our series on alternatives to knee replacement, let #39;s go over some of the growth factors needed for cartilage growth and maintenance... let #39;s talk about Fibroblast growth factor Fibroblast growth factors (FGF) are proteins that play a major role in the development of normal cartilage and bone. Genetic mutations that cause deficiencies of this protein result in significant skeletal abnormalities. In rat studies, FGF has demonstrated impressive abilities to stimulate cartilage repair in osteoarthritis. On the other hand FGF, under certain circumstances has been shown to inhibit the effects of other growth factors such as Insulin-like growth factor. Its use as an adjunctive ingredient in the application of mesenchymal stem cells for cartilage repair bears watching. http

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Stem Cells Applications in Regenerative Medicine and Disease …

Posted: November 16, 2022 at 2:34 am

Int J Cell Biol. 2016; 2016: 6940283.

Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh 462066, India

Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh 462066, India

Academic Editor: Paul J. Higgins

Received 2016 Mar 13; Accepted 2016 Jun 5.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation.

Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of specific tissue and/or organ of the patients suffering with severe injuries or chronic disease conditions, in the state where bodies own regenerative responses do not suffice [1]. In the present scenario donated tissues and organs cannot meet the transplantation demands of aged and diseased populations that have driven the thrust for search for the alternatives. Stem cells are endorsed with indefinite cell division potential, can transdifferentiate into other types of cells, and have emerged as frontline regenerative medicine source in recent time, for reparation of tissues and organs anomalies occurring due to congenital defects, disease, and age associated effects [1]. Stem cells pave foundation for all tissue and organ system of the body and mediates diverse role in disease progression, development, and tissue repair processes in host. On the basis of transdifferentiation potential, stem cells are of four types, that is, (1) unipotent, (2) multipotent, (3) pluripotent, and (4) totipotent [2]. Zygote, the only totipotent stem cell in human body, can give rise to whole organism through the process of transdifferentiation, while cells from inner cells mass (ICM) of embryo are pluripotent in their nature and can differentiate into cells representing three germ layers but do not differentiate into cells of extraembryonic tissue [2]. Stemness and transdifferentiation potential of the embryonic, extraembryonic, fetal, or adult stem cells depend on functional status of pluripotency factors like OCT4, cMYC, KLF44, NANOG, SOX2, and so forth [35]. Ectopic expression or functional restoration of endogenous pluripotency factors epigenetically transforms terminally differentiated cells into ESCs-like cells [3], known as induced pluripotent stem cells (iPSCs) [3, 4]. On the basis of regenerative applications, stem cells can be categorized as embryonic stem cells (ESCs), tissue specific progenitor stem cells (TSPSCs), mesenchymal stem cells (MSCs), umbilical cord stem cells (UCSCs), bone marrow stem cells (BMSCs), and iPSCs (; ). The transplantation of stem cells can be autologous, allogenic, and syngeneic for induction of tissue regeneration and immunolysis of pathogen or malignant cells. For avoiding the consequences of host-versus-graft rejections, tissue typing of human leucocyte antigens (HLA) for tissue and organ transplant as well as use of immune suppressant is recommended [6]. Stem cells express major histocompatibility complex (MHC) receptor in low and secret chemokine that recruitment of endothelial and immune cells is enabling tissue tolerance at graft site [6]. The current stem cell regenerative medicine approaches are founded onto tissue engineering technologies that combine the principles of cell transplantation, material science, and microengineering for development of organoid; those can be used for physiological restoration of damaged tissue and organs. The tissue engineering technology generates nascent tissue on biodegradable 3D-scaffolds [7, 8]. The ideal scaffolds support cell adhesion and ingrowths, mimic mechanics of target tissue, support angiogenesis and neovascularisation for appropriate tissue perfusion, and, being nonimmunogenic to host, do not require systemic immune suppressant [9]. Stem cells number in tissue transplant impacts upon regenerative outcome [10]; in that case prior ex vivo expansion of transplantable stem cells is required [11]. For successful regenerative outcomes, transplanted stem cells must survive, proliferate, and differentiate in site specific manner and integrate into host circulatory system [12]. This review provides framework of most recent (; Figures ) advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells as the tool of regenerative applications in wildlife conservation.

Promises of stem cells in regenerative medicine: the six classes of stem cells, that is, embryonic stem cells (ESCs), tissue specific progenitor stem cells (TSPSCs), mesenchymal stem cells (MSCs), umbilical cord stem cells (UCSCs), bone marrow stem cells (BMSCs), and induced pluripotent stem cells (iPSCs), have many promises in regenerative medicine and disease therapeutics.

ESCs in regenerative medicine: ESCs, sourced from ICM of gastrula, have tremendous promises in regenerative medicine. These cells can differentiate into more than 200 types of cells representing three germ layers. With defined culture conditions, ESCs can be transformed into hepatocytes, retinal ganglion cells, chondrocytes, pancreatic progenitor cells, cone cells, cardiomyocytes, pacemaker cells, eggs, and sperms which can be used in regeneration of tissue and treatment of disease in tissue specific manner.

TSPSCs in regenerative medicine: tissue specific stem and progenitor cells have potential to differentiate into other cells of the tissue. Characteristically inner ear stem cells can be transformed into auditory hair cells, skin progenitors into vascular smooth muscle cells, mesoangioblasts into tibialis anterior muscles, and dental pulp stem cells into serotonin cells. The 3D-culture of TSPSCs in complex biomaterial gives rise to tissue organoids, such as pancreatic organoid from pancreatic progenitor, intestinal tissue organoids from intestinal progenitor cells, and fallopian tube organoids from fallopian tube epithelial cells. Transplantation of TSPSCs regenerates targets tissue such as regeneration of tibialis muscles from mesoangioblasts, cardiac tissue from AdSCs, and corneal tissue from limbal stem cells. Cell growth and transformation factors secreted by TSPSCs can change cells fate to become other types of cell, such that SSCs coculture with skin, prostate, and intestine mesenchyme transforms these cells from MSCs into epithelial cells fate.

MSCs in regenerative medicine: mesenchymal stem cells are CD73+, CD90+, CD105+, CD34, CD45, CD11b, CD14, CD19, and CD79a cells, also known as stromal cells. These bodily MSCs represented here do not account for MSCs of bone marrow and umbilical cord. Upon transplantation and transdifferentiation these bodily MSCs regenerate into cartilage, bones, and muscles tissue. Heart scar formed after heart attack and liver cirrhosis can be treated from MSCs. ECM coating provides the niche environment for MSCs to regenerate into hair follicle, stimulating hair growth.

UCSCs in regenerative medicine: umbilical cord, the readily available source of stem cells, has emerged as futuristic source for personalized stem cell therapy. Transplantation of UCSCs to Krabbe's disease patients regenerates myelin tissue and recovers neuroblastoma patients through restoring tissue homeostasis. The UCSCs organoids are readily available tissue source for treatment of neurodegenerative disease. Peritoneal fibrosis caused by long term dialysis, tendon tissue degeneration, and defective hyaline cartilage can be regenerated by UCSCs. Intravenous injection of UCSCs enables treatment of diabetes, spinal myelitis, systemic lupus erythematosus, Hodgkin's lymphoma, and congenital neuropathies. Cord blood stem cells banking avails long lasting source of stem cells for personalized therapy and regenerative medicine.

BMSCs in regenerative medicine: bone marrow, the soft sponge bone tissue that consisted of stromal, hematopoietic, and mesenchymal and progenitor stem cells, is responsible for blood formation. Even halo-HLA matched BMSCs can cure from disease and regenerate tissue. BMSCs can regenerate craniofacial tissue, brain tissue, diaphragm tissue, and liver tissue and restore erectile function and transdifferentiation monocytes. These multipotent stem cells can cure host from cancer and infection of HIV and HCV.

iPSCs in regenerative medicine: using the edge of iPSCs technology, skin fibroblasts and other adult tissues derived, terminally differentiated cells can be transformed into ESCs-like cells. It is possible that adult cells can be transformed into cells of distinct lineages bypassing the phase of pluripotency. The tissue specific defined culture can transform skin cells to become trophoblast, heart valve cells, photoreceptor cells, immune cells, melanocytes, and so forth. ECM complexation with iPSCs enables generation of tissue organoids for lung, kidney, brain, and other organs of the body. Similar to ESCs, iPSCs also can be transformed into cells representing three germ layers such as pacemaker cells and serotonin cells.

Stem cells in wildlife conservation: tissue biopsies obtained from dead and live wild animals can be either cryopreserved or transdifferentiated to other types of cells, through culture in defined culture medium or in vivo maturation. Stem cells and adult tissue derived iPSCs have great potential of regenerative medicine and disease therapeutics. Gonadal tissue procured from dead wild animals can be matured, ex vivo and in vivo for generation of sperm and egg, which can be used for assistive reproductive technology oriented captive breeding of wild animals or even for resurrection of wildlife.

Application of stem cells in regenerative medicine: stem cells (ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs) have diverse applications in tissue regeneration and disease therapeutics.

For the first time in 1998, Thomson isolated human ESCs (hESCs) [13]. ESCs are pluripotent in their nature and can give rise to more than 200 types of cells and promises for the treatment of any kinds of disease [13]. The pluripotency fate of ESCs is governed by functional dynamics of transcription factors OCT4, SOX2, NANOG, and so forth, which are termed as pluripotency factors. The two alleles of the OCT4 are held apart in pluripotency state in ESCs; phase through homologues pairing during embryogenesis and transdifferentiation processes [14] has been considered as critical regulatory switch for lineage commitment of ESCs. The diverse lineage commitment potential represents ESCs as ideal model for regenerative therapeutics of disease and tissue anomalies. This section of review on ESCs discusses transplantation and transdifferentiation of ESCs into retinal ganglion, hepatocytes, cardiomyocytes, pancreatic progenitors, chondrocytes, cones, egg sperm, and pacemaker cells (; ). Infection, cancer treatment, and accidents can cause spinal cord injuries (SCIs). The transplantation of hESCs to paraplegic or quadriplegic SCI patients improves body control, balance, sensation, and limbal movements [15], where transplanted stem cells do homing to injury sites. By birth, humans have fixed numbers of cone cells; degeneration of retinal pigment epithelium (RPE) of macula in central retina causes age-related macular degeneration (ARMD). The genomic incorporation of COCO gene (expressed during embryogenesis) in the developing embryo leads lineage commitment of ESCs into cone cells, through suppression of TGF, BMP, and Wnt signalling pathways. Transplantation of these cone cells to eye recovers individual from ARMD phenomenon, where transplanted cone cells migrate and form sheet-like structure in host retina [16]. However, establishment of missing neuronal connection of retinal ganglion cells (RGCs), cones, and PRE is the most challenging aspect of ARMD therapeutics. Recently, Donald Z Jacks group at John Hopkins University School of Medicine has generated RGCs from CRISPER-Cas9-m-Cherry reporter ESCs [17]. During ESCs transdifferentiation process, CRIPER-Cas9 directs the knock-in of m-Cherry reporter into 3UTR of BRN3B gene, which is specifically expressed in RGCs and can be used for purification of generated RGCs from other cells [17]. Furthermore, incorporation of forskolin in transdifferentiation regime boosts generation of RGCs. Coaxing of these RGCs into biomaterial scaffolds directs axonal differentiation of RGCs. Further modification in RGCs generation regime and composition of biomaterial scaffolds might enable restoration of vision for ARMD and glaucoma patients [17]. Globally, especially in India, cardiovascular problems are a more common cause of human death, where biomedical therapeutics require immediate restoration of heart functions for the very survival of the patient. Regeneration of cardiac tissue can be achieved by transplantation of cardiomyocytes, ESCs-derived cardiovascular progenitors, and bone marrow derived mononuclear cells (BMDMNCs); however healing by cardiomyocytes and progenitor cells is superior to BMDMNCs but mature cardiomyocytes have higher tissue healing potential, suppress heart arrhythmias, couple electromagnetically into hearts functions, and provide mechanical and electrical repair without any associated tumorigenic effects [18, 19]. Like CM differentiation, ESCs derived liver stem cells can be transformed into Cytp450-hepatocytes, mediating chemical modification and catabolism of toxic xenobiotic drugs [20]. Even today, availability and variability of functional hepatocytes are a major a challenge for testing drug toxicity [20]. Stimulation of ESCs and ex vivo VitK12 and lithocholic acid (a by-product of intestinal flora regulating drug metabolism during infancy) activates pregnane X receptor (PXR), CYP3A4, and CYP2C9, which leads to differentiation of ESCs into hepatocytes; those are functionally similar to primary hepatocytes, for their ability to produce albumin and apolipoprotein B100 [20]. These hepatocytes are excellent source for the endpoint screening of drugs for accurate prediction of clinical outcomes [20]. Generation of hepatic cells from ESCs can be achieved in multiple ways, as serum-free differentiation [21], chemical approaches [20, 22], and genetic transformation [23, 24]. These ESCs-derived hepatocytes are long lasting source for treatment of liver injuries and high throughput screening of drugs [20, 23, 24]. Transplantation of the inert biomaterial encapsulated hESCs-derived pancreatic progenitors (CD24+, CD49+, and CD133+) differentiates into -cells, minimizing high fat diet induced glycemic and obesity effects in mice [25] (). Addition of antidiabetic drugs into transdifferentiation regime can boost ESCs conservation into -cells [25], which theoretically can cure T2DM permanently [25]. ESCs can be differentiated directly into insulin secreting -cells (marked with GLUT2, INS1, GCK, and PDX1) which can be achieved through PDX1 mediated epigenetic reprogramming [26]. Globally, osteoarthritis affects millions of people and occurs when cartilage at joints wears away, causing stiffness of the joints. The available therapeutics for arthritis relieve symptoms but do not initiate reverse generation of cartilage. For young individuals and athletes replacement of joints is not feasible like old populations; in that case transplantation of stem cells represents an alternative for healing cartilage injuries [27]. Chondrocytes, the cartilage forming cells derived from hESC, embedded in fibrin gel effectively heal defective cartilage within 12 weeks, when transplanted to focal cartilage defects of knee joints in mice without any negative effect [27]. Transplanted chondrocytes form cell aggregates, positive for SOX9 and collagen II, and defined chondrocytes are active for more than 12wks at transplantation site, advocating clinical suitability of chondrocytes for treatment of cartilage lesions [27]. The integrity of ESCs to integrate and differentiate into electrophysiologically active cells provides a means for natural regulation of heart rhythm as biological pacemaker. Coaxing of ESCs into inert biomaterial as well as propagation in defined culture conditions leads to transdifferentiation of ESCs to become sinoatrial node (SAN) pacemaker cells (PCs) [28]. Genomic incorporation TBox3 into ESCs ex vivo leads to generation of PCs-like cells; those express activated leukocyte cells adhesion molecules (ALCAM) and exhibit similarity to PCs for gene expression and immune functions [28]. Transplantation of PCs can restore pacemaker functions of the ailing heart [28]. In summary, ESCs can be transdifferentiated into any kinds of cells representing three germ layers of the body, being most promising source of regenerative medicine for tissue regeneration and disease therapy (). Ethical concerns limit the applications of ESCs, where set guidelines need to be followed; in that case TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs can be explored as alternatives.

TSPSCs maintain tissue homeostasis through continuous cell division, but, unlike ESCs, TSPSCs retain stem cells plasticity and differentiation in tissue specific manner, giving rise to few types of cells (). The number of TSPSCs population to total cells population is too low; in that case their harvesting as well as in vitro manipulation is really a tricky task [29], to explore them for therapeutic scale. Human body has foundation from various types of TSPSCs; discussing the therapeutic application for all types is not feasible. This section of review discusses therapeutic application of pancreatic progenitor cells (PPCs), dental pulp stem cells (DPSCs), inner ear stem cells (IESCs), intestinal progenitor cells (IPCs), limbal progenitor stem cells (LPSCs), epithelial progenitor stem cells (EPSCs), mesoangioblasts (MABs), spermatogonial stem cells (SSCs), the skin derived precursors (SKPs), and adipose derived stem cells (AdSCs) (; ). During embryogenesis PPCs give rise to insulin-producing -cells. The differentiation of PPCs to become -cells is negatively regulated by insulin [30]. PPCs require active FGF and Notch signalling; growing more rapidly in community than in single cell populations advocates the functional importance of niche effect in self-renewal and transdifferentiation processes. In 3D-scaffold culture system, mice embryo derived PPCs grow into hollow organoid spheres; those finally differentiate into insulin-producing -cell clusters [29]. The DSPSCs, responsible for maintenance of teeth health status, can be sourced from apical papilla, deciduous teeth, dental follicle, and periodontal ligaments, have emerged as regenerative medicine candidate, and might be explored for treatment of various kinds of disease including restoration neurogenic functions in teeth [31, 32]. Expansion of DSPSCs in chemically defined neuronal culture medium transforms them into a mixed population of cholinergic, GABAergic, and glutaminergic neurons; those are known to respond towards acetylcholine, GABA, and glutamine stimulations in vivo. These transformed neuronal cells express nestin, glial fibrillary acidic protein (GFAP), III-tubulin, and voltage gated L-type Ca2+ channels [32]. However, absence of Na+ and K+ channels does not support spontaneous action potential generation, necessary for response generation against environmental stimulus. All together, these primordial neuronal stem cells have possible therapeutic potential for treatment of neurodental problems [32]. Sometimes, brain tumor chemotherapy can cause neurodegeneration mediated cognitive impairment, a condition known as chemobrain [33]. The intrahippocampal transplantation of human derived neuronal stem cells to cyclophosphamide behavioural decremented mice restores cognitive functions in a month time. Here the transplanted stem cells differentiate into neuronal and astroglial lineage, reduce neuroinflammation, and restore microglial functions [33]. Furthermore, transplantation of stem cells, followed by chemotherapy, directs pyramidal and granule-cell neurons of the gyrus and CA1 subfields of hippocampus which leads to reduction in spine and dendritic cell density in the brain. These findings suggest that transplantation of stem cells to cranium restores cognitive functions of the chemobrain [33]. The hair cells of the auditory system produced during development are not postmitotic; loss of hair cells cannot be replaced by inner ear stem cells, due to active state of the Notch signalling [34]. Stimulation of inner ear progenitors with -secretase inhibitor ({"type":"entrez-nucleotide","attrs":{"text":"LY411575","term_id":"1257853995","term_text":"LY411575"}}LY411575) abrogates Notch signalling through activation of transcription factor atonal homologue 1 (Atoh1) and directs transdifferentiation of progenitors into cochlear hair cells [34]. Transplantation of in vitro generated hair cells restores acoustic functions in mice, which can be the potential regenerative medicine candidates for the treatment of deafness [34]. Generation of the hair cells also can be achieved through overexpression of -catenin and Atoh1 in Lrg5+ cells in vivo [35]. Similar to ear progenitors, intestine of the digestive tract also has its own tissue specific progenitor stem cells, mediating regeneration of the intestinal tissue [34, 36]. Dysregulation of the common stem cells signalling pathways, Notch/BMP/TGF-/Wnt, in the intestinal tissue leads to disease. Information on these signalling pathways [37] is critically important in designing therapeutics. Coaxing of the intestinal tissue specific progenitors with immune cells (macrophages), connective tissue cells (myofibroblasts), and probiotic bacteria into 3D-scaffolds of inert biomaterial, crafting biological environment, is suitable for differentiation of progenitors to occupy the crypt-villi structures into these scaffolds [36]. Omental implementation of these crypt-villi structures to dogs enhances intestinal mucosa through regeneration of goblet cells containing intestinal tissue [36]. These intestinal scaffolds are close approach for generation of implantable intestinal tissue, divested by infection, trauma, cancer, necrotizing enterocolitis (NEC), and so forth [36]. In vitro culture conditions cause differentiation of intestinal stem cells to become other types of cells, whereas incorporation of valproic acid and CHIR-99021 in culture conditions avoids differentiation of intestinal stem cells, enabling generation of indefinite pool of stem cells to be used for regenerative applications [38]. The limbal stem cells of the basal limbal epithelium, marked with ABCB5, are essential for regeneration and maintenance of corneal tissue [39]. Functional status of ABCB5 is critical for survival and functional integrity of limbal stem cells, protecting them from apoptotic cell death [39]. Limbal stem cells deficiency leads to replacement of corneal epithelium with visually dead conjunctival tissue, which can be contributed by burns, inflammation, and genetic factors [40]. Transplanted human cornea stem cells to mice regrown into fully functional human cornea, possibly supported by blood eye barrier phenomena, can be used for treatment of eye diseases, where regeneration of corneal tissue is critically required for vision restoration [39]. Muscle degenerative disease like duchenne muscular dystrophy (DMD) can cause extensive thrashing of muscle tissue, where tissue engineering technology can be deployed for functional restoration of tissue through regeneration [41]. Encapsulation of mouse or human derived MABs (engineered to express placental derived growth factor (PDGF)) into polyethylene glycol (PEG) fibrinogen hydrogel and their transplantation beneath the skin at ablated tibialis anterior form artificial muscles, which are functionally similar to those of normal tibialis anterior muscles [41]. The PDGF attracts various cell types of vasculogenic and neurogenic potential to the site of transplantation, supporting transdifferentiation of mesoangioblasts to become muscle fibrils [41]. The therapeutic application of MABs in skeletal muscle regeneration and other therapeutic outcomes has been reviewed by others [42]. One of the most important tissue specific stem cells, the male germline stem cells or spermatogonial stem cells (SSCs), produces spermatogenic lineage through mesenchymal and epithets cells [43] which itself creates niche effect on other cells. In vivo transplantation of SSCs with prostate, skin, and uterine mesenchyme leads to differentiation of these cells to become epithelia of the tissue of origin [43]. These newly formed tissues exhibit all physical and physiological characteristics of prostate and skin and the physical characteristics of prostate, skin, and uterus, express tissue specific markers, and suggest that factors secreted from SSCs lead to lineage conservation which defines the importance of niche effect in regenerative medicine [43]. According to an estimate, more than 100 million people are suffering from the condition of diabetic retinopathy, a progressive dropout of vascularisation in retina that leads to loss of vision [44]. The intravitreal injection of adipose derived stem cells (AdSCs) to the eye restores microvascular capillary bed in mice. The AdSCs from healthy donor produce higher amounts of vasoprotective factors compared to glycemic mice, enabling superior vascularisation [44]. However use of AdSCs for disease therapeutics needs further standardization for cell counts in dose of transplant and monitoring of therapeutic outcomes at population scale [44]. Apart from AdSCs, other kinds of stem cells also have therapeutic potential in regenerative medicine for treatment of eye defects, which has been reviewed by others [45]. Fallopian tubes, connecting ovaries to uterus, are the sites where fertilization of the egg takes place. Infection in fallopian tubes can lead to inflammation, tissue scarring, and closure of the fallopian tube which often leads to infertility and ectopic pregnancies. Fallopian is also the site where onset of ovarian cancer takes place. The studies on origin and etiology of ovarian cancer are restricted due to lack of technical advancement for culture of epithelial cells. The in vitro 3D organoid culture of clinically obtained fallopian tube epithelial cells retains their tissue specificity, keeps cells alive, which differentiate into typical ciliated and secretory cells of fallopian tube, and advocates that ectopic examination of fallopian tube in organoid culture settings might be the ideal approach for screening of cancer [46]. The sustained growth and differentiation of fallopian TSPSCs into fallopian tube organoid depend both on the active state of the Wnt and on paracrine Notch signalling [46]. Similar to fallopian tube stem cells, subcutaneous visceral tissue specific cardiac adipose (CA) derived stem cells (AdSCs) have the potential of differentiation into cardiovascular tissue [47]. Systemic infusion of CA-AdSCs into ischemic myocardium of mice regenerates heart tissue and improves cardiac function through differentiation to endothelial cells, vascular smooth cells, and cardiomyocytes and vascular smooth cells. The differentiation and heart regeneration potential of CA-AdSCs are higher than AdSCs [48], representing CA-AdSCs as potent regenerative medicine candidates for myocardial ischemic therapy [47]. The skin derived precursors (SKPs), the progenitors of dermal papilla/hair/hair sheath, give rise to multiple tissues of mesodermal and/or ectodermal origin such as neurons, Schwann cells, adipocytes, chondrocytes, and vascular smooth muscle cells (VSMCs). VSMCs mediate wound healing and angiogenesis process can be derived from human foreskin progenitor SKPs, suggesting that SKPs derived VSMCs are potential regenerative medicine candidates for wound healing and vasculature injuries treatments [49]. In summary, TSPSCs are potentiated with tissue regeneration, where advancement in organoid culture (; ) technologies defines the importance of niche effect in tissue regeneration and therapeutic outcomes of ex vivo expanded stem cells.

MSCs, the multilineage stem cells, differentiate only to tissue of mesodermal origin, which includes tendons, bone, cartilage, ligaments, muscles, and neurons [50]. MSCs are the cells which express combination of markers: CD73+, CD90+, CD105+, CD11b, CD14, CD19, CD34, CD45, CD79a, and HLA-DR, reviewed elsewhere [50]. The application of MSCs in regenerative medicine can be generalized from ongoing clinical trials, phasing through different state of completions, reviewed elsewhere [90]. This section of review outlines the most recent representative applications of MSCs (; ). The anatomical and physiological characteristics of both donor and receiver have equal impact on therapeutic outcomes. The bone marrow derived MSCs (BMDMSCs) from baboon are morphologically and phenotypically similar to those of bladder stem cells and can be used in regeneration of bladder tissue. The BMDMSCs (CD105+, CD73+, CD34, and CD45), expressing GFP reporter, coaxed with small intestinal submucosa (SIS) scaffolds, augment healing of degenerated bladder tissue within 10wks of the transplantation [51]. The combinatorial CD characterized MACs are functionally active at transplantation site, which suggests that CD characterization of donor MSCs yields superior regenerative outcomes [51]. MSCs also have potential to regenerate liver tissue and treat liver cirrhosis, reviewed elsewhere [91]. The regenerative medicinal application of MSCs utilizes cells in two formats as direct transplantation or first transdifferentiation and then transplantation; ex vivo transdifferentiation of MSCs deploys retroviral delivery system that can cause oncogenic effect on cells. Nonviral, NanoScript technology, comprising utility of transcription factors (TFs) functionalized gold nanoparticles, can target specific regulatory site in the genome effectively and direct differentiation of MSCs into another cell fate, depending on regime of TFs. For example, myogenic regulatory factor containing NanoScript-MRF differentiates the adipose tissue derived MSCs into muscle cells [92]. The multipotency characteristics represent MSCs as promising candidate for obtaining stable tissue constructs through coaxed 3D organoid culture; however heterogeneous distribution of MSCs slows down cell proliferation, rendering therapeutic applications of MSCs. Adopting two-step culture system for MSCs can yield homogeneous distribution of MSCs in biomaterial scaffolds. For example, fetal-MSCs coaxed in biomaterial when cultured first in rotating bioreactor followed with static culture lead to homogeneous distribution of MSCs in ECM components [7]. Occurrence of dental carries, periodontal disease, and tooth injury can impact individual's health, where bioengineering of teeth can be the alternative option. Coaxing of epithelial-MSCs with dental stem cells into synthetic polymer gives rise to mature teeth unit, which consisted of mature teeth and oral tissue, offering multiple regenerative therapeutics, reviewed elsewhere [52]. Like the tooth decay, both human and animals are prone to orthopedic injuries, affecting bones, joint, tendon, muscles, cartilage, and so forth. Although natural healing potential of bone is sufficient to heal the common injuries, severe trauma and tumor-recession can abrogate germinal potential of bone-forming stem cells. In vitro chondrogenic, osteogenic, and adipogenic potential of MSCs advocates therapeutic applications of MSCs in orthopedic injuries [53]. Seeding of MSCs, coaxed into biomaterial scaffolds, at defective bone tissue, regenerates defective bone tissues, within fourwks of transplantation; by the end of 32wks newly formed tissues integrate into old bone [54]. Osteoblasts, the bone-forming cells, have lesser actin cytoskeleton compared to adipocytes and MSCs. Treatment of MSCs with cytochalasin-D causes rapid transportation of G-actin, leading to osteogenic transformation of MSCs. Furthermore, injection of cytochalasin-D to mice tibia also promotes bone formation within a wk time frame [55]. The bone formation processes in mice, dog, and human are fundamentally similar, so outcomes of research on mice and dogs can be directional for regenerative application to human. Injection of MSCs to femur head of Legg-Calve-Perthes suffering dog heals the bone very fast and reduces the injury associated pain [55]. Degeneration of skeletal muscle and muscle cramps are very common to sledge dogs, animals, and individuals involved in adventurous athletics activities. Direct injection of adipose tissue derived MSCs to tear-site of semitendinosus muscle in dogs heals injuries much faster than traditional therapies [56]. Damage effect treatment for heart muscle regeneration is much more complex than regeneration of skeletal muscles, which needs high grade fine-tuned coordination of neurons with muscles. Coaxing of MSCs into alginate gel increases cell retention time that leads to releasing of tissue repairing factors in controlled manner. Transplantation of alginate encapsulated cells to mice heart reduces scar size and increases vascularisation, which leads to restoration of heart functions. Furthermore, transplanted MSCs face host inhospitable inflammatory immune responses and other mechanical forces at transplantation site, where encapsulation of cells keeps them away from all sorts of mechanical forces and enables sensing of host tissue microenvironment, and respond accordingly [57]. Ageing, disease, and medicine consumption can cause hair loss, known as alopecia. Although alopecia has no life threatening effects, emotional catchments can lead to psychological disturbance. The available treatments for alopecia include hair transplantation and use of drugs, where drugs are expensive to afford and generation of new hair follicle is challenging. Dermal papillary cells (DPCs), the specialized MSCs localized in hair follicle, are responsible for morphogenesis of hair follicle and hair cycling. The layer-by-layer coating of DPCs, called GAG coating, consists of coating of geletin as outer layer, middle layer of fibroblast growth factor 2 (FGF2) loaded alginate, and innermost layer of geletin. GAG coating creates tissue microenvironment for DPCs that can sustain immunological and mechanical obstacles, supporting generation of hair follicle. Transplantation of GAG-coated DPCs leads to abundant hair growth and maturation of hair follicle, where GAG coating serves as ECM, enhancing intrinsic therapeutic potential of DPCs [58]. During infection, the inflammatory cytokines secreted from host immune cells attract MSCs to the site of inflammation, which modulates inflammatory responses, representing MSCs as key candidate of regenerative medicine for infectious disease therapeutics. Coculture of macrophages (M) and adipose derived MSCs from Leishmania major (LM) susceptible and resistant mice demonstrates that AD-MSCs educate M against LM infection, differentially inducing M1 and M2 phenotype that represents AD-MSC as therapeutic agent for leishmanial therapy [93]. In summary, the multilineage differentiation potential of MSCs, as well as adoption of next-generation organoid culture system, avails MSCs as ideal regenerative medicine candidate.

Umbilical cord, generally thrown at the time of child birth, is the best known source for stem cells, procured in noninvasive manner, having lesser ethical constraints than ESCs. Umbilical cord is rich source of hematopoietic stem cells (HSCs) and MSCs, which possess enormous regeneration potential [94] (; ). The HSCs of cord blood are responsible for constant renewal of all types of blood cells and protective immune cells. The proliferation of HSCs is regulated by Musashi-2 protein mediated attenuation of Aryl hydrocarbon receptor (AHR) signalling in stem cells [95]. UCSCs can be cryopreserved at stem cells banks (; ), in operation by both private and public sector organization. Public stem cells banks operate on donation formats and perform rigorous screening for HLA typing and donated UCSCs remain available to anyone in need, whereas private stem cell banks operation is more personalized, availing cells according to donor consent. Stem cell banking is not so common, even in developed countries. Survey studies find that educated women are more eager to donate UCSCs, but willingness for donation decreases with subsequent deliveries, due to associated cost and safety concerns for preservation [96]. FDA has approved five HSCs for treatment of blood and other immunological complications [97]. The amniotic fluid, drawn during pregnancy for standard diagnostic purposes, is generally discarded without considering its vasculogenic potential. UCSCs are the best alternatives for those patients who lack donors with fully matched HLA typing for peripheral blood and PBMCs and bone marrow [98]. One major issue with UCSCs is number of cells in transplant, fewer cells in transplant require more time for engraftment to mature, and there are also risks of infection and mortality; in that case ex vivo propagation of UCSCs can meet the demand of desired outcomes. There are diverse protocols, available for ex vivo expansion of UCSCs, reviewed elsewhere [99]. Amniotic fluid stem cells (AFSCs), coaxed to fibrin (required for blood clotting, ECM interactions, wound healing, and angiogenesis) hydrogel and PEG supplemented with vascular endothelial growth factor (VEGF), give rise to vascularised tissue, when grafted to mice, suggesting that organoid cultures of UCSCs have promise for generation of biocompatible tissue patches, for treating infants born with congenital heart defects [59]. Retroviral integration of OCT4, KLF4, cMYC, and SOX2 transforms AFSCs into pluripotency stem cells known as AFiPSCs which can be directed to differentiate into extraembryonic trophoblast by BMP2 and BMP4 stimulation, which can be used for regeneration of placental tissues [60]. Wharton's jelly (WJ), the gelatinous substance inside umbilical cord, is rich in mucopolysaccharides, fibroblast, macrophages, and stem cells. The stem cells from UCB and WJ can be transdifferentiated into -cells. Homogeneous nature of WJ-SCs enables better differentiation into -cells; transplantation of these cells to streptozotocin induced diabetic mice efficiently brings glucose level to normal [7]. Easy access and expansion potential and plasticity to differentiate into multiple cell lineages represent WJ as an ideal candidate for regenerative medicine but cells viability changes with passages with maximum viable population at 5th-6th passages. So it is suggested to perform controlled expansion of WJ-MSCS for desired regenerative outcomes [9]. Study suggests that CD34+ expression leads to the best regenerative outcomes, with less chance of host-versus-graft rejection. In vitro expansion of UCSCs, in presence of StemRegenin-1 (SR-1), conditionally expands CD34+ cells [61]. In type I diabetic mellitus (T1DM), T-cell mediated autoimmune destruction of pancreatic -cells occurs, which has been considered as tough to treat. Transplantation of WJ-SCs to recent onset-T1DM patients restores pancreatic function, suggesting that WJ-MSCs are effective in regeneration of pancreatic tissue anomalies [62]. WJ-MSCs also have therapeutic importance for treatment of T2DM. A non-placebo controlled phase I/II clinical trial demonstrates that intravenous and intrapancreatic endovascular injection of WJ-MSCs to T2DM patients controls fasting glucose and glycated haemoglobin through improvement of -cells functions, evidenced by enhanced c-peptides and reduced inflammatory cytokines (IL-1 and IL-6) and T-cells counts [63]. Like diabetes, systematic lupus erythematosus (SLE) also can be treated with WJ-MSCs transplantation. During progression of SLE host immune system targets its own tissue leading to degeneration of renal, cardiovascular, neuronal, and musculoskeletal tissues. A non-placebo controlled follow-up study on 40 SLE patients demonstrates that intravenous infusion of WJ-MSC improves renal functions and decreases systematic lupus erythematosus disease activity index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), and repeated infusion of WJ-MSCs protects the patient from relapse of the disease [64]. Sometimes, host inflammatory immune responses can be detrimental for HSCs transplantation and blood transfusion procedures. Infusion of WJ-MSC to patients, who had allogenic HSCs transplantation, reduces haemorrhage inflammation (HI) of bladder, suggesting that WJ-MSCs are potential stem cells adjuvant in HSCs transplantation and blood transfusion based therapies [100]. Apart from WJ, umbilical cord perivascular space and cord vein are also rich source for obtaining MSCs. The perivascular MSCs of umbilical cord are more primitive than WJ-MSCs and other MSCs from cord suggest that perivascular MSCs might be used as alternatives for WJ-MSCs for regenerative therapeutics outcome [101]. Based on origin, MSCs exhibit differential in vitro and in vivo properties and advocate functional characterization of MSCs, prior to regenerative applications. Emerging evidence suggests that UCSCs can heal brain injuries, caused by neurodegenerative diseases like Alzheimer's, Krabbe's disease, and so forth. Krabbe's disease, the infantile lysosomal storage disease, occurs due to deficiency of myelin synthesizing enzyme (MSE), affecting brain development and cognitive functions. Progression of neurodegeneration finally leads to death of babies aged two. Investigation shows that healing of peripheral nervous system (PNS) and central nervous system (CNS) tissues with Krabbe's disease can be achieved by allogenic UCSCs. UCSCs transplantation to asymptomatic infants with subsequent monitoring for 46 years reveals that UCSCs recover babies from MSE deficiency, improving myelination and cognitive functions, compared to those of symptomatic babies. The survival rate of transplanted UCSCs in asymptomatic and symptomatic infants was 100% and 43%, respectively, suggesting that early diagnosis and timely treatment are critical for UCSCs acceptance for desired therapeutic outcomes. UCSCs are more primitive than BMSCs, so perfect HLA typing is not critically required, representing UCSCs as an excellent source for treatment of all the diseases involving lysosomal defects, like Krabbe's disease, hurler syndrome, adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), Tay-Sachs disease (TSD), and Sandhoff disease [65]. Brain injuries often lead to cavities formation, which can be treated from neuronal parenchyma, generated ex vivo from UCSCs. Coaxing of UCSCs into human originated biodegradable matrix scaffold and in vitro expansion of cells in defined culture conditions lead to formation of neuronal organoids, within threewks' time frame. These organoids structurally resemble brain tissue and consisted of neuroblasts (GFAP+, Nestin+, and Ki67+) and immature stem cells (OCT4+ and SOX2+). The neuroblasts of these organoids further can be differentiated into mature neurons (MAP2+ and TUJ1+) [66]. Administration of high dose of drugs in divesting neuroblastoma therapeutics requires immediate restoration of hematopoiesis. Although BMSCs had been promising in restoration of hematopoiesis UCSCs are sparely used in clinical settings. A case study demonstrates that neuroblastoma patients who received autologous UCSCs survive without any associated side effects [12]. During radiation therapy of neoplasm, spinal cord myelitis can occur, although occurrence of myelitis is a rare event and usually such neurodegenerative complication of spinal cord occurs 624 years after exposure to radiations. Transplantation of allogenic UC-MSCs in laryngeal patients undergoing radiation therapy restores myelination [102]. For treatment of neurodegenerative disease like Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), traumatic brain injuries (TBI), Parkinson's, SCI, stroke, and so forth, distribution of transplanted UCSCs is critical for therapeutic outcomes. In mice and rat, injection of UCSCs and subsequent MRI scanning show that transplanted UCSCs migrate to CNS and multiple peripheral organs [67]. For immunomodulation of tumor cells disease recovery, transplantation of allogenic DCs is required. The CD11c+DCs, derived from UCB, are morphologically and phenotypically similar to those of peripheral blood derived CTLs-DCs, suggesting that UCB-DCs can be used for personalized medicine of cancer patient, in need for DCs transplantation [103]. Coculture of UCSCs with radiation exposed human lung fibroblast stops their transdifferentiation, which suggests that factors secreted from UCSCs may restore niche identity of fibroblast, if they are transplanted to lung after radiation therapy [104]. Tearing of shoulder cuff tendon can cause severe pain and functional disability, whereas ultrasound guided transplantation of UCB-MSCs in rabbit regenerates subscapularis tendon in fourwks' time frame, suggesting that UCB-MSCs are effective enough to treat tendons injuries when injected to focal points of tear-site [68]. Furthermore, transplantation of UCB-MSCs to chondral cartilage injuries site in pig knee along with HA hydrogel composite regenerates hyaline cartilage [69], suggesting that UCB-MSCs are effective regenerative medicine candidate for treating cartilage and ligament injuries. Physiologically circulatory systems of brain, placenta, and lungs are similar. Infusion of UCB-MSCs to preeclampsia (PE) induced hypertension mice reduces the endotoxic effect, suggesting that UC-MSCs are potential source for treatment of endotoxin induced hypertension during pregnancy, drug abuse, and other kinds of inflammatory shocks [105]. Transplantation of UCSCs to severe congenital neutropenia (SCN) patients restores neutrophils count from donor cells without any side effect, representing UCSCs as potential alternative for SCN therapy, when HLA matched bone marrow donors are not accessible [106]. In clinical settings, the success of myocardial infarction (MI) treatment depends on ageing, systemic inflammation in host, and processing of cells for infusion. Infusion of human hyaluronan hydrogel coaxed UCSCs in pigs induces angiogenesis, decreases scar area, improves cardiac function at preclinical level, and suggests that the same strategy might be effective for human [107]. In stem cells therapeutics, UCSCs transplantation can be either autologous or allogenic. Sometimes, the autologous UCSCs transplants cannot combat over tumor relapse, observed in Hodgkin's lymphoma (HL), which might require second dose transplantation of allogenic stem cells, but efficacy and tolerance of stem cells transplant need to be addressed, where tumor replace occurs. A case study demonstrates that second dose allogenic transplants of UCSCs effective for HL patients, who had heavy dose in prior transplant, increase the long term survival chances by 30% [10]. Patients undergoing long term peritoneal renal dialysis are prone to peritoneal fibrosis and can change peritoneal structure and failure of ultrafiltration processes. The intraperitoneal (IP) injection of WJ-MSCs prevents methylglyoxal induced programmed cell death and peritoneal wall thickening and fibrosis, suggesting that WJ-MSCs are effective in therapeutics of encapsulating peritoneal fibrosis [70]. In summary, UCB-HSCs, WJ-MSCs, perivascular MSCs, and UCB-MSCs have tissue regeneration potential.

Bone marrow found in soft spongy bones is responsible for formation of all peripheral blood and comprises hematopoietic stem cells (producing blood cells) and stromal cells (producing fat, cartilage, and bones) [108] (; ). Visually bone marrow has two types, red marrow (myeloid tissue; producing RBC, platelets, and most of WBC) and yellow marrow (producing fat cells and some WBC) [108]. Imbalance in marrow composition can culminate to the diseased condition. Since 1980, bone marrow transplantation is widely accepted for cancer therapeutics [109]. In order to avoid graft rejection, HLA typing of donors is a must, but completely matched donors are limited to family members, which hampers allogenic transplantation applications. Since matching of all HLA antigens is not critically required, in that case defining the critical antigens for haploidentical allogenic donor for patients, who cannot find fully matched donor, might relieve from donor constraints. Two-step administration of lymphoid and myeloid BMSCs from haploidentical donor to the patients of aplastic anaemia and haematological malignancies reconstructs host immune system and the outcomes are almost similar to fully matched transplants, which recommends that profiling of critically important HLA is sufficient for successful outcomes of BMSCs transplantation. Haploidentical HLA matching protocol is the major process for minorities and others who do not have access to matched donor [71]. Furthermore, antigen profiling is not the sole concern for BMSCs based therapeutics. For example, restriction of HIV1 (human immune deficiency virus) infection is not feasible through BMSCs transplantation because HIV1 infection is mediated through CD4+ receptors, chemokine CXC motif receptor 4 (CXCR4), and chemokine receptor 5 (CCR5) for infecting and propagating into T helper (Th), monocytes, macrophages, and dendritic cells (DCs). Genetic variation in CCR2 and CCR5 receptors is also a contributory factor; mediating protection against infection has been reviewed elsewhere [110]. Engineering of hematopoietic stem and progenitor cells (HSPCs) derived CD4+ cells to express HIV1 antagonistic RNA, specifically designed for targeting HIV1 genome, can restrict HIV1 infection, through immune elimination of latently infected CD4+ cells. A single dose infusion of genetically modified (GM), HIV1 resistant HSPCs can be the alternative of HIV1 retroviral therapy. In the present scenario stem cells source, patient selection, transplantation-conditioning regimen, and postinfusion follow-up studies are the major factors, which can limit application of HIV1 resistant GM-HSPCs (CD4+) cells application in AIDS therapy [72, 73]. Platelets, essential for blood clotting, are formed from megakaryocytes inside the bone marrow [74]. Due to infection, trauma, and cancer, there are chances of bone marrow failure. To an extent, spongy bone marrow microenvironment responsible for lineage commitment can be reconstructed ex vivo [75]. The ex vivo constructed 3D-scaffolds consisted of microtubule and silk sponge, flooded with chemically defined organ culture medium, which mimics bone marrow environment. The coculture of megakaryocytes and embryonic stem cells (ESCs) in this microenvironment leads to generation of functional platelets from megakaryocytes [75]. The ex vivo 3D-scaffolds of bone microenvironment can stride the path for generation of platelets in therapeutic quantities for regenerative medication of burns [75] and blood clotting associated defects. Accidents, traumatic injuries, and brain stroke can deplete neuronal stem cells (NSCs), responsible for generation of neurons, astrocytes, and oligodendrocytes. Brain does not repopulate NSCs and heal traumatic injuries itself and transplantation of BMSCs also can heal neurodegeneration alone. Lipoic acid (LA), a known pharmacological antioxidant compound used in treatment of diabetic and multiple sclerosis neuropathy when combined with BMSCs, induces neovascularisation at focal cerebral injuries, within 8wks of transplantation. Vascularisation further attracts microglia and induces their colonization into scaffold, which leads to differentiation of BMSCs to become brain tissue, within 16wks of transplantation. In this approach, healing of tissue directly depends on number of BMSCs in transplantation dose [76]. Dental caries and periodontal disease are common craniofacial disease, often requiring jaw bone reconstruction after removal of the teeth. Traditional therapy focuses on functional and structural restoration of oral tissue, bone, and teeth rather than biological restoration, but BMSCs based therapies promise for regeneration of craniofacial bone defects, enabling replacement of missing teeth in restored bones with dental implants. Bone marrow derived CD14+ and CD90+ stem and progenitor cells, termed as tissue repair cells (TRC), accelerate alveolar bone regeneration and reconstruction of jaw bone when transplanted in damaged craniofacial tissue, earlier to oral implants. Hence, TRC therapy reduces the need of secondary bone grafts, best suited for severe defects in oral bone, skin, and gum, resulting from trauma, disease, or birth defects [77]. Overall, HSCs have great value in regenerative medicine, where stem cells transplantation strategies explore importance of niche in tissue regeneration. Prior to transplantation of BMSCs, clearance of original niche from target tissue is necessary for generation of organoid and organs without host-versus-graft rejection events. Some genetic defects can lead to disorganization of niche, leading to developmental errors. Complementation with human blastocyst derived primary cells can restore niche function of pancreas in pigs and rats, which defines the concept for generation of clinical grade human pancreas in mice and pigs [111]. Similar to other organs, diaphragm also has its own niche. Congenital defects in diaphragm can affect diaphragm functions. In the present scenario functional restoration of congenital diaphragm defects by surgical repair has risk of reoccurrence of defects or incomplete restoration [8]. Decellularization of donor derived diaphragm offers a way for reconstruction of new and functionally compatible diaphragm through niche modulation. Tissue engineering technology based decellularization of diaphragm and simultaneous perfusion of bone marrow mesenchymal stem cells (BM-MSCs) facilitates regeneration of functional scaffolds of diaphragm tissues [8]. In vivo replacement of hemidiaphragm in rats with reseeded scaffolds possesses similar myography and spirometry as it has in vivo in donor rats. These scaffolds retaining natural architecture are devoid of immune cells, retaining intact extracellular matrix that supports adhesion, proliferation, and differentiation of seeded cells [8]. These findings suggest that cadaver obtained diaphragm, seeded with BM-MSCs, can be used for curing patients in need for restoration of diaphragm functions (; ). However, BMSCs are heterogeneous population, which might result in differential outcomes in clinical settings; however clonal expansion of BMSCs yields homogenous cells population for therapeutic application [8]. One study also finds that intracavernous delivery of single clone BMSCs can restore erectile function in diabetic mice [112] and the same strategy might be explored for adult human individuals. The infection of hepatitis C virus (HCV) can cause liver cirrhosis and degeneration of hepatic tissue. The intraparenchymal transplantation of bone marrow mononuclear cells (BMMNCs) into liver tissue decreases aspartate aminotransferase (AST), alanine transaminase (ALT), bilirubin, CD34, and -SMA, suggesting that transplanted BMSCs restore hepatic functions through regeneration of hepatic tissues [113]. In order to meet the growing demand for stem cells transplantation therapy, donor encouragement is always required [8]. The stem cells donation procedure is very simple; with consent donor gets an injection of granulocyte-colony stimulating factor (G-CSF) that increases BMSCs population. Bone marrow collection is done from hip bone using syringe in 4-5hrs, requiring local anaesthesia and within a wk time frame donor gets recovered donation associated weakness.

The field of iPSCs technology and research is new to all other stem cells research, emerging in 2006 when, for the first time, Takahashi and Yamanaka generated ESCs-like cells through genetic incorporation of four factors, Sox2, Oct3/4, Klf4, and c-Myc, into skin fibroblast [3]. Due to extensive nuclear reprogramming, generated iPSCs are indistinguishable from ESCs, for their transcriptome profiling, epigenetic markings, and functional competence [3], but use of retrovirus in transdifferentiation approach has questioned iPSCs technology. Technological advancement has enabled generation of iPSCs from various kinds of adult cells phasing through ESCs or direct transdifferentiation. This section of review outlines most recent advancement in iPSC technology and regenerative applications (; ). Using the new edge of iPSCs technology, terminally differentiated skin cells directly can be transformed into kidney organoids [114], which are functionally and structurally similar to those of kidney tissue in vivo. Up to certain extent kidneys heal themselves; however natural regeneration potential cannot meet healing for severe injuries. During kidneys healing process, a progenitor stem cell needs to become 20 types of cells, required for waste excretion, pH regulation, and restoration of water and electrolytic ions. The procedure for generation of kidney organoids ex vivo, containing functional nephrons, has been identified for human. These ex vivo kidney organoids are similar to fetal first-trimester kidneys for their structure and physiology. Such kidney organoids can serve as model for nephrotoxicity screening of drugs, disease modelling, and organ transplantation. However generation of fully functional kidneys is a far seen event with today's scientific technologies [114]. Loss of neurons in age-related macular degeneration (ARMD) is the common cause of blindness. At preclinical level, transplantation of iPSCs derived neuronal progenitor cells (NPCs) in rat limits progression of disease through generation of 5-6 layers of photoreceptor nuclei, restoring visual acuity [78]. The various approaches of iPSCs mediated retinal regeneration including ARMD have been reviewed elsewhere [79]. Placenta, the cordial connection between mother and developing fetus, gets degenerated in certain pathophysiological conditions. Nuclear programming of OCT4 knock-out (KO) and wild type (WT) mice fibroblast through transient expression of GATA3, EOMES, TFAP2C, and +/ cMYC generates transgene independent trophoblast stem-like cells (iTSCs), which are highly similar to blastocyst derived TSCs for DNA methylation, H3K7ac, nucleosome deposition of H2A.X, and other epigenetic markings. Chimeric differentiation of iTSCs specifically gives rise to haemorrhagic lineages and placental tissue, bypassing pluripotency phase, opening an avenue for generation of fully functional placenta for human [115]. Neurodegenerative disease like Alzheimer's and obstinate epilepsies can degenerate cerebrum, controlling excitatory and inhibitory signals of the brain. The inhibitory tones in cerebral cortex and hippocampus are accounted by -amino butyric acid secreting (GABAergic) interneurons (INs). Loss of these neurons often leads to progressive neurodegeneration. Genomic integration of Ascl1, Dlx5, Foxg1, and Lhx6 to mice and human fibroblast transforms these adult cells into GABAergic-INs (iGABA-INs). These cells have molecular signature of telencephalic INs, release GABA, and show inhibition to host granule neuronal activity [81]. Transplantation of these INs in developing embryo cures from genetic and acquired seizures, where transplanted cells disperse and mature into functional neuronal circuits as local INs [82]. Dorsomorphin and SB-431542 mediated inhibition of TGF- and BMP signalling direct transformation of human iPSCs into cortical spheroids. These cortical spheroids consisted of both peripheral and cortical neurons, surrounded by astrocytes, displaying transcription profiling and electrophysiology similarity with developing fetal brain and mature neurons, respectively [83]. The underlying complex biology and lack of clear etiology and genetic reprogramming and difficulty in recapitulation of brain development have barred understanding of pathophysiology of autism spectrum disorder (ASD) and schizophrenia. 3D organoid cultures of ASD patient derived iPSC generate miniature brain organoid, resembling fetal brain few months after gestation. The idiopathic conditions of these organoids are similar with brain of ASD patients; both possess higher inhibitory GABAergic neurons with imbalanced neuronal connection. Furthermore these organoids express forkhead Box G1 (FOXG1) much higher than normal brain tissue, which explains that FOXG1 might be the leading cause of ASD [84]. Degeneration of other organs and tissues also has been reported, like degeneration of lungs which might occur due to tuberculosis infection, fibrosis, and cancer. The underlying etiology for lung degeneration can be explained through organoid culture. Coaxing of iPSC into inert biomaterial and defined culture leads to formation of lung organoids that consisted of epithelial and mesenchymal cells, which can survive in culture for months. These organoids are miniature lung, resemble tissues of large airways and alveoli, and can be used for lung developmental studies and screening of antituberculosis and anticancer drugs [87]. The conventional multistep reprogramming for iPSCs consumes months of time, while CRISPER-Cas9 system based episomal reprogramming system that combines two steps together enables generation of ESCs-like cells in less than twowks, reducing the chances of culture associated genetic abrasions and unwanted epigenetic [80]. This approach can yield single step ESCs-like cells in more personalized way from adults with retinal degradation and infants with severe immunodeficiency, involving correction for genetic mutation of OCT4 and DNMT3B [80]. The iPSCs expressing anti-CCR5-RNA, which can be differentiated into HIV1 resistant macrophages, have applications in AIDS therapeutics [88]. The diversified immunotherapeutic application of iPSCs has been reviewed elsewhere [89]. The -1 antitrypsin deficiency (A1AD) encoded by serpin peptidase inhibitor clade A member 1 (SERPINA1) protein synthesized in liver protects lungs from neutrophils elastase, the enzyme causing disruption of lungs connective tissue. A1AD deficiency is common cause of both lung and liver disease like chronic obstructive pulmonary disease (COPD) and liver cirrhosis. Patient specific iPSCs from lung and liver cells might explain pathophysiology of A1AD deficiency. COPD patient derived iPSCs show sensitivity to toxic drugs which explains that actual patient might be sensitive in similar fashion. It is known that A1AD deficiency is caused by single base pair mutation and correction of this mutation fixes the A1AD deficiency in hepatic-iPSCs [85]. The high order brain functions, like emotions, anxiety, sleep, depression, appetite, breathing heartbeats, and so forth, are regulated by serotonin neurons. Generation of serotonin neurons occurs prior to birth, which are postmitotic in their nature. Any sort of developmental defect and degeneration of serotonin neurons might lead to neuronal disorders like bipolar disorder, depression, and schizophrenia-like psychiatric conditions. Manipulation of Wnt signalling in human iPSCs in defined culture conditions leads to an in vitro differentiation of iPSCs to serotonin-like neurons. These iPSCs-neurons primarily localize to rhombomere 2-3 segment of rostral raphe nucleus, exhibit electrophysiological properties similar to serotonin neurons, express hydroxylase 2, the developmental marker, and release serotonin in dose and time dependent manner. Transplantation of these neurons might cure from schizophrenia, bipolar disorder, and other neuropathological conditions [116]. The iPSCs technology mediated somatic cell reprogramming of ventricular monocytes results in generation of cells, similar in morphology and functionality with PCs. SA note transplantation of PCs to large animals improves rhythmic heart functions. Pacemaker needs very reliable and robust performance so understanding of transformation process and site of transplantation are the critical aspect for therapeutic validation of iPSCs derived PCs [28]. Diabetes is a major health concern in modern world, and generation of -cells from adult tissue is challenging. Direct reprogramming of skin cells into pancreatic cells, bypassing pluripotency phase, can yield clinical grade -cells. This reprogramming strategy involves transformation of skin cells into definitive endodermal progenitors (cDE) and foregut like progenitor cells (cPF) intermediates and subsequent in vitro expansion of these intermediates to become pancreatic -cells (cPB). The first step is chemically complex and can be understood as nonepisomal reprogramming on day one with pluripotency factors (OCT4, SOX2, KLF4, and hair pin RNA against p53), then supplementation with GFs and chemical supplements on day seven (EGF, bFGF, CHIR, NECA, NaB, Par, and RG), and two weeks later (Activin-A, CHIR, NECA, NaB, and RG) yielding DE and cPF [86]. Transplantation of cPB yields into glucose stimulated secretion of insulin in diabetic mice defines that such cells can be explored for treatment of T1DM and T2DM in more personalized manner [86]. iPSCs represent underrated opportunities for drug industries and clinical research laboratories for development of therapeutics, but safety concerns might limit transplantation applications (; ) [117]. Transplantation of human iPSCs into mice gastrula leads to colonization and differentiation of cells into three germ layers, evidenced with clinical developmental fat measurements. The acceptance of human iPSCs by mice gastrula suggests that correct timing and appropriate reprogramming regime might delimit human mice species barrier. Using this fact of species barrier, generation of human organs in closely associated primates might be possible, which can be used for treatment of genetic factors governed disease at embryo level itself [118]. In summary, iPSCs are safe and effective for treatment of regenerative medicine.

The unstable growth of human population threatens the existence of wildlife, through overexploitation of natural habitats and illegal killing of wild animals, leading many species to face the fate of being endangered and go for extinction. For wildlife conservation, the concept of creation of frozen zoo involves preservation of gene pool and germ plasm from threatened and endangered species (). The frozen zoo tissue samples collection from dead or live animal can be DNA, sperms, eggs, embryos, gonads, skin, or any other tissue of the body [119]. Preserved tissue can be reprogrammed or transdifferentiated to become other types of tissues and cells, which opens an avenue for conservation of endangered species and resurrection of life (). The gonadal tissue from young individuals harbouring immature tissue can be matured in vivo and ex vivo for generation of functional gametes. Transplantation of SSCs to testis of male from the same different species can give rise to spermatozoa of donor cells [120], which might be used for IVF based captive breeding of wild animals. The most dangerous fact in wildlife conservation is low genetic diversity, too few reproductively capable animals which cannot maintain adequate genetic diversity in wild or captivity. Using the edge of iPSC technology, pluripotent stem cells can be generated from skin cells. For endangered drill, Mandrillus leucophaeus, and nearly extinct white rhinoceros, Ceratotherium simum cottoni, iPSC has been generated in 2011 [121]. The endangered animal drill (Mandrillus leucophaeus) is genetically very close to human and often suffers from diabetes, while rhinos are genetically far removed from other primates. The progress in iPSCs, from the human point of view, might be transformed for animal research for recapturing reproductive potential and health in wild animals. However, stem cells based interventions in wild animals are much more complex than classical conservation planning and biomedical research has to face. Conversion of iPSC into egg or sperm can open the door for generation of IVF based embryo; those might be transplanted in womb of live counterparts for propagation of population. Recently, iPSCs have been generated for snow leopard (Panthera uncia), native to mountain ranges of central Asia, which belongs to cat family; this breakthrough has raised the possibilities for cryopreservation of genetic material for future cloning and other assisted reproductive technology (ART) applications, for the conservation of cat species and biodiversity. Generation of leopard iPSCs has been achieved through retroviral-system based genomic integration of OCT4, SOX2, KLF4, cMYC, and NANOG. These iPSCs from snow leopard also open an avenue for further transformation of iPSCs into gametes [122]. The in vivo maturation of grafted tissue depends both on age and on hormonal status of donor tissue. These facts are equally applicable to accepting host. Ectopic xenografts of cryopreserved testis tissue from Indian spotted deer (Moschiola indica) to nude mice yielded generation of spermatocytes [123], suggesting that one-day procurement of functional sperm from premature tissue might become a general technique in wildlife conservation. In summary, tissue biopsies from dead or live animals can be used for generation of iPSCs and functional gametes; those can be used in assisted reproductive technology (ART) for wildlife conservation.

The spectacular progress in the field of stem cells research represents great scope of stem cells regenerative therapeutics. It can be estimated that by 2020 or so we will be able to produce wide array of tissue, organoid, and organs from adult stem cells. Inductions of pluripotency phenotypes in terminally differentiated adult cells have better therapeutic future than ESCs, due to least ethical constraints with adult cells. In the coming future, there might be new pharmaceutical compounds; those can activate tissue specific stem cells, promote stem cells to migrate to the side of tissue injury, and promote their differentiation to tissue specific cells. Except few countries, the ongoing financial and ethical hindrance on ESCs application in regenerative medicine have more chance for funding agencies to distribute funding for the least risky projects on UCSCs, BMSCs, and TSPSCs from biopsies. The existing stem cells therapeutics advancements are more experimental and high in cost; due to that application on broad scale is not feasible in current scenario. In the near future, the advancements of medical science presume using stem cells to treat cancer, muscles damage, autoimmune disease, and spinal cord injuries among a number of impairments and diseases. It is expected that stem cells therapies will bring considerable benefits to the patients suffering from wide range of injuries and disease. There is high optimism for use of BMSCs, TSPSCs, and iPSCs for treatment of various diseases to overcome the contradictions associated with ESCs. For advancement of translational application of stem cells, there is a need of clinical trials, which needs funding rejoinder from both public and private organizations. The critical evaluation of regulatory guidelines at each phase of clinical trial is a must to comprehend the success and efficacy in time frame.

Dr. Anuradha Reddy from Centre for Cellular and Molecular Biology Hyderabad and Mrs. Sarita Kumari from Department of Yoga Science, BU, Bhopal, India, are acknowledged for their critical suggestions and comments on paper.

There are no competing interests associated with this paper.

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Stem-cell therapy and platelet-rich plasma in regenerative …

Posted: January 5, 2022 at 2:00 am

J Oral Maxillofac Pathol. 2018 Sep-Dec; 22(3): 367374.

1Department of Oral Pathology, MMNG Halgekar Institute of Dental Science, Belagavi, Karnataka, India

2Center for Incubation, Innovation, Research and Consultancy, Jyothy Institute of Technology, Bengaluru, Karnataka, India

3Department of Oral Pathologist, Chaitanya Dental Clinic, Bengaluru, Karnataka, India

4General and Laparoscopic Surgeon, SSNMC Hospital, Bengaluru, Karnataka, India

1Department of Oral Pathology, MMNG Halgekar Institute of Dental Science, Belagavi, Karnataka, India

2Center for Incubation, Innovation, Research and Consultancy, Jyothy Institute of Technology, Bengaluru, Karnataka, India

3Department of Oral Pathologist, Chaitanya Dental Clinic, Bengaluru, Karnataka, India

4General and Laparoscopic Surgeon, SSNMC Hospital, Bengaluru, Karnataka, India

Received 2018 Sep 3; Accepted 2018 Sep 6.

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Regenerative medicine encompasses new emerging branch of medical sciences that involves the functional restoration of tissues or organs caused by severe injuries or chronic diseases. Currently, there are two contending technologies that can repair and restore the damaged tissues, namely platelet-rich plasma (PRP)- and stem cell (SC)-based therapies. PRP is a component of blood that contains platelet concentrations above the normal level and includes platelet-related growth factors and plasma-derived fibrinogen. Platelets are the frontline healing response to injuries as they release growth factors for tissue repair. SCs, on the other hand, are the unspecialized, undifferentiated, immature cells that based on specific stimuli can divide and differentiate into specific type of cells and tissues. Differentiated SCs can divide and replace the worn out or damaged tissues to become tissue- or organ-specific cells with specialized functions. Despite these differences, both approaches rely on rejuvenating the damaged tissue. This review is focused on delineating the preparation procedures, similarities and disparities and advantages and disadvantages of PRP- and SC-based therapies.

Keywords: Platelet-rich plasma, regeneration, stem cells, treatment

Regenerative medicine is a major part of the rapidly emerging biomedical research over the last decade which mainly involves the development of new therapeutic strategies resulting in greater advancement in the field. These recent biomedical approaches have provided the tenacity for medical community to look for alternatives to conventional therapies. Among the several therapeutic strategies available, the use of platelet-rich plasma (PRP) and stem cell (SC) represents the mainstream technologies to repair and rejuvenate the damaged tissue caused due to injury or chronic diseases.[1] PRP is the component of the blood (plasma) which contains five times higher concentrations of platelets above the normal values, i.e., PRP is the volume of autologous plasma that has the platelet concentration above the baseline.[2] Platelets are the tiny components of blood that are rich in growth factors and play a crucial role by forming blood clots during injury. It is a well-known fact that wound healing of damaged tissues depends on the platelet concentrations. PRP acts by nurturing those cells that can heal on their own or can augment the healing process by the resolution of damaged tissues. One of the widely used applications of PRP is in the regeneration and reconstruction of skeletal and connective tissues in the periodontal and maxillofacial diseases and in sports-related injuries.[3,4] Unlike PRP, SCs are the primitive cells that are obtained either from embryos or from the adult tissues. SC has the capacity of self-renewal and can differentiate into as many as 200 different cell types of the adult body.[5] Besides these properties, SC also produces certain growth factors and cytokines that accelerate the healing process at the site of tissue damage. Therapeutic applications of SC include treating many degenerative and inflammatory conditions by replacing the damaged cells in virtually any tissue or organ, where PRP applications serve no benefit.

Although both PRP- and SC-based therapies are destined to perform similar functions in restoring the damaged tissue to function normally, there exists a vast difference in their preparation procedures and their functionality []. SC is isolated from the adult tissues and cultured in sophisticated settings and requires several weeks to grow before they could be used for therapeutics. Contrary to SC, preparation of PRP is simple and involves rapid separation from blood and does not contain SCs for therapeutics per se. Furthermore, compared to SC-based therapies, the curative potential of PRP is considerably lower and regenerative potential is limited to the cells present in such tissues. Due to the similarity in function and the rapid preparations of PRP, several clinicians persuade patients to prefer PRP-based approaches citing that it is similar to SC-based therapies. Considering the existence of such a paradigm between the use of PRP- and SC-based technologies, future research should focus on understanding and clearly defining the molecular mechanism in tissue regeneration. In addition, efficacy and the perseverance of preparative methods, consensus in the preparation methods among different research groups for clinical applications and the significance of such technologies as a substitute for conventional therapies should be delineated and appropriately implemented.[4]

The differences between platelet-rich plasma and stem-cell therapy

The term PRP was introduced in the 1970s to describe the autologous preparations and enrichment of platelets from plasma concentrate.[6] Platelets also known as thrombocytes are produced from megakaryocytes in mammalian bone marrow.[7] They form a first line of cellular defense response following damage to vascular and tissue integrity and play a crucial role in homeostasis, innate immunity, angiogenesis and wound healing.[8,9,10] Under normal conditions, the typical blood samples contain approximately 94% of red blood cells (RBCs), 6% of platelets and 1% of white blood cells. The whole purpose of enriching for PRP is to reverse the RBC-to-platelet ratio to achieve 95% platelets and 5% of RBCs.[11] Enriched fraction of PRP is known to contain high level of growth factors and cytokines that promote tissue regeneration and healing and also reported to be effective in tissue reparative efficacy.[12]

The primary roles of platelets are to form aggregated and also contribute to homeostasis through adhesion, activation and aggregation. Previously, platelets were thought to have only hemostatic activity. However, recent advancement has provided a new perspective on platelet function in regulating inflammation, angiogenesis, SC migration and cell proliferation.[6] Although many studies have supported the beneficial effects of using PRP, the Food and Drug Administration approval for injections of PRP is still under consideration. The only adverse reaction reported is transient pain and localized swelling after injections, but the overall adverse reactions being very low. Further studies are required to assess the efficacy of use of PRP for therapy and its possible long-term adverse reactions.

Platelets play an important role in healing at the site of injury. The increased number of platelets results in increased number of secreted growth factors, thereby increasing the healing process. This phenomenon is attributed as it promotes mitogenesis of healing capable cells and angiogenesis in the tissues. Along with the presence of growth factors, they also contain adhesion molecules that include fibrin, fibronectin and vitronectin which help promote bone formation.[13,14] PRP preparations also play a role in revascularization of damaged tissue by promoting cell migration, proliferation, differentiation and stabilization of endothelial cells in new blood vessels. PRP also restores damaged connective tissue by promoting the migration, proliferation and activation of fibroblasts.[15,16] Platelets also host a vast reservoir of over 800 proteins which when secreted act upon SCs, fibroblasts, osteoblasts and endothelial and epithelial cells.[12] The main purpose of using PRP for therapeutics originated from the idea to deliver the growth factors, cytokines and -granules to the site of injury, which acts as cell cycle regulators, and promote healing process across variety of tissues.[8]

The PRP preparations are known to contain many growth factors, chemokines and cytokines [] which induce the downstream signaling pathways that ultimately lead to synthesis of proteins necessary for collagen, osteoid and extracellular matrix formation.[17] PRP also has numerous cell adhesion molecules including fibrin, fibronectin, vitronectin and thrombospondin that trigger the assimilation of osteoblasts, fibroblasts and epithelial cells. Apart from its role in structural and functional healing, PRP preparations are also been implicated in the reduced use of narcotics, improved sleep and reduction in pain perception.[6,18,19]

The components of platelet-rich plasma and their functions

Preparation of PRP for regeneration of tissues includes three sequential steps blood collection, PRP separation and PRP activation. Briefly, blood is collected using the anticoagulant agent preferably using acid citrate dextrose. The blood is then centrifugation using highly variable protocols with varying time (420 min), velocities (1003000 g), temperature (12C26C) and cycles of centrifugation (1 or 2 cycles). Due to these variable protocols, the platelet concentrations are enriched anywhere between 5 and 9 times. After centrifugation, the blood is separated into three layers the bottom layer (RBCs), middle layer (platelets and white blood cells) and top layer (plasma with gradient of platelet concentrations) [].[11,15]

The procedure of separation of platelet-rich plasma from the venous blood

Considering different parameters and clinical applications, PRP is further classified base on four categories: activated, nonactivated, leukocyte rich and leukocyte poor. Activated PRP is prepared with calcium chloride with or without thrombin, which leads to release of cytokines from the granules in platelets. Nonactivated PRP preparations include platelet contact with intrinsic collagen and thromboplastin, which activate the platelets within connective tissue. In addition, the presence of leukocytes plays a role in inhibiting bacterial growth by improving soft-tissue healing, which would have been hindered by infection.[13] Magalon in 2016 proposed a DEAP classification which is based on dose, efficiency, purity and activation of platelets.[6] Further studies have been carried out to characterize and classify PRP based on preparation (centrifugation and use of anticoagulant), content (platelets, leukocytes and growth factors) and clinical applications. Studies by Dohan Ehrenfest et al. have proposed PRP classifications based on the presence and absence of leukocytes and fibrin architecture.[20]

Pure PRP: Preparations show low-density fibrin network after activation

Leukocyte- and PRP: Preparations contain leukocytes and exhibit low-density fibrin network after activation

Pure platelet-rich fibrin: Preparations lack leukocytes and have high-density fibrin network and exist in activated gel form

Leukocyte- and platelet-rich fibrin: Preparations have leukocytes with high-density fibrin network.

Over the last few years, the use of PRP as a therapeutic tool has made a significant advancement in the field of regenerative medicine particularly in the field of wound healing and skin regeneration, dentistry, cosmetic and plastic surgery, fat grafting, bone regeneration, tendinopathies, ophthalmology, hepatocyte recovery, esthetic surgery, orthopedics, soft-tissue ulcers and skeletal muscle injury and others.[8]

As PRP contains high concentrations of growth factors, it is widely used for hair regrowth. These growth factors promote hair regrowth by binding to their respective receptors expressed by SCs of the hair follicle bulge region and associated tissues.[12]

The application of PRP in dermatology has increased in tissue regeneration, wound healing, scar revision and skin rejuvenating effects. PRP has rich source of growth factors that promote mitogenic, angiogenic and chemotactic properties; it has been used for the treatment of recalcitrant wounds. In cosmetic dermatology, PRP is known to stimulate human dermal fibroblast proliferation and increase type I collagen synthesis. In addition, injections of PRP into deep dermal layers have induced soft-tissue augmentation, activation of fibroblasts, new collagen deposition, new blood vessels and adipose tissue formation. Studies have also shown that PRP along with other techniques has improved the quality of the skin and leads to an increase in collagen and elastic fibers.[6]

PRP has also been used predominantly for musculoskeletal regeneration caused during sports injury. Acute hamstring for injuries accounts for approximately 29% of all sports-related injuries where PRP-based treatments have shown beneficial effects. Patellar tendinopathy also known as jumper's knee is the most common cause of anterior knee pain among athletes. Application of PRP is known to promote repair and reduce inflammation.[6] Achilles tendinopathy is another sports injury associated with severe pain and swelling at the tendinous insertion site. The rupture might get worse without proper treatment. Currently, muscle-strengthening exercise and anti-inflammatory medications are the only treatment options. The use of PRP was proposed as a treatment option.[13]

Osteoarthritis is one of the most common knee disorders which are commonly seen in elderly people due to cartilage damage and inflammatory changes. Several meta-analysis conducted on the these patients using both leukocyte-rich and leukocyte-poor PRP has displayed the benefits in favor of using PRP for osteoarthritis. PRP is known to stimulate chondrocytes and synoviocytes to produce cartilage matrix. In rotator cuff tear, which is the most common cause of shoulder disability, the inclusion of PRP-based therapy has beneficial effects for tendinous injuries. However, further clinical trials and metadata analysis are required for the clinical use of PRP as effective treatment technologies.[13] Apart from these diseases, PRP has also known to suppress the growth of particular species of bacteria such as Staphylococcus aureus.[21] It is also shown to improve endometrial thickness in patients undergoing in vitro fertilization treatment.[22]

In conclusion, there is an increase in the evidence that shows the beneficial use of platelet-based applications in tissue regeneration. However, there is considerable debate on the effectiveness of platelet-based applications, especially between human- and animal-based studies which could be due to the methodological differences among different research groups. There is a tremendous possibility for exploration in regenerative medicine which could use PRP for potential therapeutic applications.

The major advantage of the use of PRP for therapeutic applications is the immediate preparation of PRP, which does not require any preservative facilities. PRP is considered safe and natural as the preparation involves using own cells without any further modifications. This also ensures that the preparations do not elicit immune response. Since the preparations are from the same person, the chances of getting the bloodborne contaminations are minimized. As a large number of populations succumb to musculoskeletal injuries or disorders, application of PRP-based therapies has shown promising results.[11,23]

The use of PRP as such does not have major demerits. However, under certain circumstances, PRP applications can result in injection-site morbidity, infection or injury to nerves or blood vessels. Scar tissue formation and calcification at the injection site have also been reported. Some patients have also experienced acute ache or soreness at the site of injection and also in the muscle or deeper areas such as the bone. Patients with compromised immune system or with predisposed diseases are more susceptible to infection at the injured area. Studies have reported allergic reactions among few individuals who have taken PRP-enriched fractions. Since PRP is given intravenously, the chances of damaging the artery or veins which could result in blood clot exist. Studies have also advised against using PRP-based therapies among individuals with a history of heavy smoking and drug and alcohol use and patients diagnosed with platelet dysfunction syndromes, thrombocytopenia, hyperfibrinogenemia, hemodynamic instability, sepsis, acute and chronic infections, chronic liver disease, anticoagulation therapy, chronic skin diseases or cancer and metabolic and systemic disorders due to the complications associated with the PRP-based treatment.[11]

Recent advancement in the SC research has emphasized on the use of adult SC (ASC)-based therapies, which were not cured by conventional medicines. Tissue-resident adult progenitor SCs have clinical importance due to their potential cell sources for transplantation in regenerative medicine and cancer therapies. The ability for indefinite self-renewal and multilineage differentiation into other types of cells represents SCs, which offers great promise in replacing the nonfunctional or lost cells to regenerate damaged or diseased tissues.[24] The use of small subpopulation of adult stem or progenitor cells from tissues or organs from the same individual provides the possibility of stimulating those in vivo differentiation or cell replacement and gene therapies with multiple applications in humans without the risk of graft rejection. Research on tissue-resident SCs has explored the clinical interest in cell replacement-based therapies in regenerative medicine and cancer therapies.[25]

Based on their origin, SCs are divided into two types embryonic SCs (ESCs) and ASCs. ESCs are derived from epiblast of the blastocyst from which many tissues of embryo arise, whereas ASCs are localized in adult organs [] where these cells function to replace damaged cells during tissue regeneration.[26,27] SCs are further classified into four types based on their transdifferentiation potential which include totipotent, pluripotent, multipotent and unipotent SC.[24] ESCs are known to have totipotent and pluripotent in nature and have the ability to differentiate into cells of three germ layers endoderm, mesoderm and ectoderm.[28] ASC is multipotent and can give rise to differentiated cells of anyone germ layer.[29] Unipotent SCs arise from multipotent cells and are dedicated to differentiate into specific type of tissue, for example, precursors for cardiomyocytes present in human heart or satellite cells characteristic for skeletal muscles are dedicated to differentiate into specific tissue.[30]

Source and Type of cells produced from a normal adult stem cells

The use of SCs for therapeutic purposes was proposed as early in the 1960s because of their inherent ability to differentiate into multiple cell lines.[17] This requires careful isolation and culturing which has to be done in aseptic condition. SCs are extracted either from bone marrow or fat tissue and are sometimes used in conjunction with platelets. Once isolated, SCs can retain their ability to transform into a variety of cell types. So far, there is no standardized procedure to isolate and to characterize SCs; however, specific markers are available to identify them.[31] Mesenchymal SCs (MSCs) are extensively studied cell types in regenerative medicine due to their immunomodulatory properties.[32] Studies have shown that MSC has the capacity to differentiate into osteocytes, adipocytes, myocytes and cells of chondrogenic lineage.[17] MSCs express markers that include CD73, CD90 and CD105 (endoglin) but not CD11b, CD14, CD19, CD34, CD45, CD79a and human leukocyte antigen Class II.[33] Hematopoietic SCs express two important hematopoietic markers, i.e., CD45 and CD34.[34] Certain markers have been used as pluripotent markers such as OCT4, NANOG and SOX2. OCT4 is a transcriptional factor involved in early embryogenesis and very much essential for maintenance of pluripotency of SCs.[35] NANOG is a transcription factor and is involved in self-renewal capacity of undifferentiated SCs and has the ability to form any cell type of three germ layers of human body.[36,37] The third pluripotency gene is sex-determining region SOX2 which is also a transcription factor and maintains self-renew capacity of undifferentiated SCs.[38]

Although the use of SC has immense medical benefits, their applications in many diseases are still in the research and clinical trial phase and further studies are required for its long-term use in clinical settings. SCs have much more potent regulatory role in immune system. Compared to PRP-based approach, SC therapy can be very promising in treatment of many degenerative diseases where PRP is not suitable. SCs are also been used to treat many dental-related disorders such as regeneration and reconstruction of dental and oromaxillofacial tissues.[39,40] MSCs have shown to support blood and lymphangiogenesis and also shown to act as precursors of endothelial cells and pericytes and promote angiogenesis.[41] MSCs are known to orchestrate wound repair by cellular differentiation, immune modulation and production of growth factors that drive neovascularization and re-epithelialization [].

The promise of stem-cell therapy in regenerative medicine

SC-based therapies are emerging as a powerful tool for treating many degenerative and inflammatory diseases. Apart from differentiating into new tissue that is lost, they also coordinate in repair response. SC can be isolated from patients and can be amenable to autologous transplantation. Treatment with single isolation can provide lifetime repository of cells for the patients. Furthermore, SC can be genetically modified to overexpress crucial genes that can augment wound healing and decrease the formation of scars.[42]

Although SC has added advantage over PRP-based approach in regenerating the damaged tissue, there are certain concerns in using SC for therapies. SC propensity toward self-renewal and differentiation is highly influenced by their local environment making it difficult to interpret how a population of culture expands MSC may behave in vivo. Isolation and characterization of SC are crucial and even the isolated SC may have low survival rates. Culturing of SC without contamination requires highly experienced personnel and sophisticated laboratory settings. The chances of microbial contamination of SC might result in complications, especially in those patients whose immune system is compromised. Careful monitoring and observation of this cell-based therapy are of paramount importance, since evidence has shown that adipose-derived MSCs have lost genetic stability over time and were prone to tumor formation.[43] Based on the specific application, SC should be differentiated into appropriate cell types before they can be clinically used, failure of which may have deleterious effects. Furthermore, SC-based therapies require regular follow-up to monitor regenerated tissue over a period of complete recovery of a patient. In vivo niches, SCs are present under hypoxic conditions and change in oxygen levels can induce oxidative stress, which can influence SC phenotype, proliferation, fate, pluripotency, etc., Therefore, in vitro culture conditions used to study MSCs should be maintained similar to their in vivo niches.[44]

PRP and SC therapy is continuously studied for their regenerative benefit in wound healing, sports medicine and chronic pain treatment. Although their preparation, mechanism and action and efficacy have been shown to be different, studies have shown that both PRP and SC can complement each other and might have an added advantage when used in combination. For example, PRP offers a suitable microenvironment for MSCs to promote proliferation and differentiation and accelerates wound healing capabilities. Conversely, PRP can be a powerful tool to attract cell populations, such as MSCs, a combination of which provides a promising approach for the treatment.[45] Some of the common injuries that are treated using combinational therapy include tendonitis, rotator cuff tears, osteoarthritis, spine conditions, arthritic joints, overuse injuries, inflammation from herniated disc and others.[46,47]

Despite many beneficial effects of PRP in treating clinical conditions and with minimal side effects, the use of PRP as a regenerative medicine is still in its infancy. The major constraint is the limited availability of adequate controlled clinical trials and lack of consensus related to PRP preparation techniques. Nevertheless, the use of PRP-based preparations has shown promising results in some clinical settings, especially in the field of dermatology, dentistry, ophthalmology, orthopedics and others. Future research has to be focused on understanding the molecular mechanisms involved in the PRP-based therapies in tissue regeneration and long-term side effects associated with the use of PRP. Optimum concentration required to attain maximum tissue regeneration response without eliciting the immune response has to be determined. Investigating these key questions would increase the use of PRP-based regenerative medicines in treating acute and chronic ailments rather than using conventional therapies which would include surgeries followed by prolonged supportive therapies.

Although PRP and SC represent a promising treatment for many diseases, large-scale clinical trials using both in vitro and in vivo studies are required to establish the true effectiveness of the treatments. SC-based therapies have shown promising results in clinical settings, and further work should be carried out to optimize the transplantation procedures that ensure functional integration, proliferation, differentiation and migration of transplanted tissue-specific ASCs to repair and replace the damaged tissue and their long-term survival in the tissue niche.

In conclusion, PRP-based therapeutic option could be used as an alternative form of therapy alone or in combination with other conventional treatments. In this regard, it is important to understand the formulations and specific enrichment fractions that could be suitable for particular treatment. Furthermore, research has to focus on standardizing the PRP formulations and have a consensus data from the clinical trials from different research groups for better prognosis and to use as an alternative to conventional therapies.

Nil.

There are no conflicts of interest.

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Orthopedics – Pennsylvania Stem Cell Center

Posted: May 25, 2020 at 8:44 am

As an alternative to orthopedic surgery, patients traditionally seek treatments such as an injection of cartilage substitutes or steroids. Despite some short-term relief, steroids actually damage tissues over time and are not a viable long-term option.

Joint Osteoarthritis is the degeneration of the joint components, both cartilage and bone. Experts agree that stem cells may help in the repair of osteoarthritis in many ways, since they may act as anti-inflammatory mediators, or forming new cartilage or bone cells, by differentiation. Each individual patient will be evaluated to determine the potential success with stem cell therapy.

Patients coping with arthritis, sports injuries, tendon strains, sprained ligaments, muscle injuries and more, will be comforted to know that surgery is not the only option of treatment available to them. Faster healing as well as improved functionality both are possible with innovative, cutting- edge adult stem cell treatments.

There are breakthroughs in non-surgical treatments for people suffering from knee pain due to common injuries to the knee meniscus, ACL or MCL. If you are experiencing cartilage damage or degenerative conditions, such as osteoarthritis, traditional options for patients suffering from these conditions include

Now, there are new ways to aid in the destruction of cartilage in your knees. Results show alternatives to surgery and Stem Cell Therapy is being recommended by more scientists and doctors every week. Stem cell research offers unprecedented opportunities for developing new treatments for debilitating diseases for which there are few or no cures. Among the knee injuries and conditions that may be treated with stem cells include:

Osteoarthritis (OA) is a degenerative joint disease that can affect any joint in your body, including your hips. Over time, due to aging, trauma or other factors, the cartilage that cushions your joints starts to break down. Without cartilage, your joint bones rub together when you move. The bone-on-bone action creates pain, stiffness, and can limit your mobility. This is especially true with OA of the hip, as the hip contains large joints that carry your bodys weight with each step you take. Treatment options for hip arthritis range from lifestyle modifications to pain management, exercise programs, and even surgery.

Non-surgical stem cell injection procedures happen within a single day and may offer a viable alternative for those who are facing surgery or hip replacement. Patients are far less vulnerable to the serious risks associated with traumatic hip surgeries, such as infection and blood clots.

Our patients quickly return to normal activity following their procedure and are able to avoid the painful and lengthy rehabilitation periods that are required following hip surgery to help restore

A common sources of shoulder pain is arthritis: which is a degenerative process causing pain, swelling, stiffness, and disability. Minor shoulder issues, for example, sore muscles and a throbbing painfulness, are regular. Shoulder pain develops from ordinary wear and tear, overuse, or a damage.

At PA Stem Cell Centers, we are a leading non-surgical specialist for chronic shoulder pain and injuries from:

As ankle pain and ankle arthritis surgery alternatives, stem cell therapy may help alleviate the cause of pain with simple office injection procedure. Patients are encouraged to walk the same day, and most experience almost no down time after the procedure.

At PA Stem Cell Centers, we are a non-surgical specialists for chronic ankle pain and injuries from:

PA Stem Cell Treatment Centers offer non-surgical, stem cell treatments for patients who are suffering from wrist and hand pain or may be facing wrist or hand surgery due to ligament injury, tendonitis, bone injuries, arthritis, bursitis and other medical conditions.

If you have an injury or pain in your hand or wrist from ligament or tendon sprains or tear, or due to osteoarthritis, you may be a candidate for stem cell therapy. At PA Stem Cell Therapy, we are leading non-surgical specialist for chronic wrist and hand pain and injuries from:

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Orthopedics - Pennsylvania Stem Cell Center

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Indiana Regenerative Medicine Institute Offers Innovative Approaches in Regenerative Medicine, Hormone Replacement and Pain Management – Zionsville…

Posted: February 29, 2020 at 9:45 am

February 2020

Are you looking for a health care provider who offers innovative alternatives and a customized approach to your health issues? Indiana Regenerative Medicine Institute (IRMI) believes in offering specialized alternatives to health care. Its medical team, headed by Doctor of Chiropractic Preston Peachee, utilizes the latest developments in regenerative medicine, hormone replacement and pain management.

Dr. Peachee is a native of Jasper, Indiana. He graduatedfrom Logan College of Chiropractic and has been in practice since 2003. Hisareas of specialty include patients with chronic and severe back, neck andjoint pain as well as other complex neurological conditions.

Dr. Peachee has earned a reputation as an innovative thinkeras well as a compassionate practitioner who brings his wide expertise andexperience to the Greater Indianapolis area. His ability to help those in needof regenerative medicine, neuropathy pain relief, low testosterone or otherphysical ailments, such as back pain or fibromyalgia, makes him not only uniquebut highly sought-after.

A key member of the IRMI team is Leann Emery, FNP. Emery isa family nurse practitioner with more than 20 years of experience in hormonereplacement and alternative pain management. Emery provides optimal patientcare through personal consultations and assessments to identify her patientsspecific health needs. She was rated in the top 10% of providers in the U.S.with patient satisfaction.

Regenerative medicine is making huge leaps in our understanding of the human body, and it is offering real, possible treatments that would have seemed like science fiction a few short years ago, according to IRMI. Most patients we see have tried other more traditional treatments and have either not gotten any better or have gotten even worse. Unfortunately, a lot of people we see depend on multiple medications per day to try and function but still are not happy with how they feel or how they live their lives. It is unfortunately the nature of deteriorating and degenerative joints, they will get worse with time, and generally the pain increases as well.

Depending on the injury, Dr. Peachee will often combinelaser therapy with the regenerative medicine protocols to improve the outcomesand try and speed the recovery process.

We offer mesenchymal stem cell therapy, Dr. Peachee said. With the combination of laser therapy, mesenchymal stem cell therapy is incredibly effective for rotator cuff problems and treating knee pain. Eighty percent of our stem patients are dealing with knee pain or Osteoarthritis. Osteoarthritis-or O.A. of the knee- is a huge problem for a lot of people, and we get great results from these therapies. Most people can even avoidknee surgery.

Dr. Peachee recently introduced hormone treatments for low testosterone. Family Nurse Practitioner Leann Emery has been doing [hormone] treatments for 20 years, and that area of medicine became a natural fit for IRMI.

I have several patients who were seeking this type ofcaremany who are police officers and firefighterswho couldnt find thetherapy and individualized care and attention that they needed.

Dr. Peachee explained that low T treatments help patients with unique and even complicated cases of Erectile Dysfunction (E.D.). Most people seek us out for treatment because they are tired, worn out, stressed out and just simply lack the energy they used to have.

We are able to fill a niche with patients who hadcomplicated cases that were not responding well with their primary careproviders or other places, Dr. Peachee shared. We have a patient who hasstruggled for a long time with fertility issues but has done very well [withtreatments], and we just got good news that he and his wife are expecting aftertrying for a really long time. So, he is really enthused about that.

The typical candidates for low T treatments, according toDr. Peachee, are men who feel worn out, are lethargic and have lost theirzest for life.

Our patients dont have the same pep that they had 10 or20 years ago, Dr. Peachee stated. They struggle getting up in the morning andmight be struggling in the afternoon after having six cups of coffee or threeRed Bulls just to get through the day. We have a lot of people that want to getback into the gym and get the maximum benefit of their workouts. We can helpthem improve their overall health and energy so that they can enjoyrecreational activities like working out or practice with the Little Leaguewith their kids. Many times we hear from spouses, friends and family how muchbetter they feel and that they seem happier and get more out of life again.

It goes without saying that proper hormonal balance canimprove a patients personal relationships as well and improve the overallmental health of a patient by reducing stress, anxiety and depression oftencaused by symptoms related to low testosterone levels.

We focus on injectable [low T] treatments because we canmodify the dosage and give more frequent doses to keep our patients at a levelthats going to give them the maximum benefit and improvement for theirconditions, Dr. Peachee explained.

With the modern changes in medicine over the last 20 and 50years, were helping people to live a lot longer and adding 20 to 30 years totheir lives, but we have not given them an improved quality of life as theyage. By working with their hormones and getting them in balance, their qualityof life becomes way better, and were seeing a positive improvement for manypeople with these treatments.

Patients suffering from severe disc injuries, such a bulgingor herniated disc or discs, or who suffer from degenerative disc disease mayhave undergone treatment from chiropractors or have seen physical therapistsbefore coming to Indiana Regenerative Medicine Institute.

Our typical patient who comes in for this type of treatmenthas seen other therapists or chiropractors but hasnt found lasting relief,Dr. Peachee said. Many of our patients want to get off the rollercoaster ofopioids and pain medications. They are looking for a solution without narcoticsand risk of addiction or other possible negative side effects of narcoticsand/or surgery. We are generally able to alleviate the pain in 90% of patientsand are able to keep them from having surgery or from taking addictivemedications.

Laser therapy allows Dr. Peachee to work on the damaged tissue so that it can heal, and the method reduces inflammation and swelling in a way that traditional treatments cannot.

Its an innovative new therapy within the last decade thatallows us to do some amazing things, Dr. Peachee stated. We perform ourprocedures in our office and have several different devices for the specificneeds and issues of our patients. For instance, we have a unique device forpeople with knee pain that can help the majority of our patients walk betterand live more pain-free. We get a phenomenal outcome with this procedure.

One of the other major differentiators that sets IndianaRegenerative Medicine Institute apart from other offices and clinics is thatthey are advocates for their patients, especially when it comes to dealing withtheir patients insurance providers.

A lot of our low T patients are able to get their insurancecarriers to cover the services so that it doesnt cost them as much out ofpocket for the care they seek, Dr. Peachee said. Weve partnered with abilling company that has helped us to be able to navigate the craziness of ourmodern insurance companies, and by doing so, were able to keep the cost downfor a lot of patients. Not every insurance plan will cover this type of care,but a lot of them will. When its possible and ethical, we do whatever we canto benefit our patients to help keep the cost low. I have spent a lot of freetime writing letters on behalf of our patients. We go above and beyond with ourservice and care of our patients.

The Indiana Regenerative Medicine Institute team will make housecalls or come to a patients place of work when the situation calls for thatlevel of care.

We will go and draw blood for blood work, bring medications and even do exams in some situations, Dr. Peachee said. As I mentioned before, we see a lot of police officers and firemen all over the statefrom Mishawaka to South Bend and all over Indiana. We go once a month to see these patients at their departments and stations so that we see them all in one day versus making 10 to 15 guys drive hours to come in to see us. Its a service we can offer because we are a small clinic and we are focused on that one-on-one patient attention and relationship building. We have great relationships with our patients, and thats something that we work very hard at.

Building trust and transparency is crucial to the success ofhis practice, Dr. Peachee emphasized. The trust that we build with ourpatients is crucial to not only the success of the practice but to thepatients outcomes. And not just with hormone therapy but also with ournonsurgical spinal decompression patients. These are patients with significant discinjuries, and we need them to tell us everything we need to know so we can givemore accurate and complete care for a better outcome.

I would say to anybody if you have any doubts or reservations to take some of the burden and some of the anxiety out of the equation and schedule an initial consultationabsolutely free of charge, Dr. Peachee encouraged.

Dont put off living your best life any longer. Visit Indiana Regenerative Medicine Institutes website at indianaregen.com or call (317) 653-4503 for more information about its services and specialized treatments and schedule your free consultationtoday!

Writer:

Janelle Morrison

Photography:

Laura Arick and submitted

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Indiana Regenerative Medicine Institute Offers Innovative Approaches in Regenerative Medicine, Hormone Replacement and Pain Management - Zionsville...

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Stem Cell Treatment Rhode Island – Boston Stem Cell Center

Posted: September 7, 2019 at 4:26 pm

Stem cell treatment can treat a wide array of medical conditions. Learn more about what we can treat by reading the information below:

Constant knee problems can make it challenging to move from one part of your house to another. Some doctors may recommend knee surgery, knee joint replacement or a knee athroplasty to treat the pain in your knees.

However, choosing to undergo surgery may entail a long recovery time. After your operation, you may need to stay in the hospital for a few days. Moreover, you might not be allowed to drive or carry heavy things for the next 3 months.

Stem cell treatment is one method to help heal our body naturally. Found throughout our body, stem cells can developed into different cells, such as cartilage cells that can help joints. We use your stem cells for this procedure that we extract from the bone marrow in your hip bone. After that, we inject the cells together with platelet-rich plasma back into your knee.

Injuries, arthritis, and bursitis are some causes of hip pain. Without proper treatment, this can impair your movement and even cause difficulty in sleeping.

Hip surgery or hip joint replacement are common procedures for hip pain, mobility problems, and more. However, they may not have lasting effects. For example, you may need another hip replacement surgery after about 10 to 15 years.

At the Boston Stem Cell Center, we offer stem cell treatments as an alternative for patients experiencing hip pain. We use your own stem cells to help heal hip joints and help other local repair processes. Our stem cell treatment can help reduce inflammation, provide pain relief, and improve function.

Osteoarthritis and rotator cuff tendon tear are some reasons why you may experience shoulder pain. Sometimes, nonsurgical treatment such as medications may not be enough to alleviate the pain. Your doctor may recommend surgery if you are experiencing chronic pain.

If you are looking for alternatives to surgery, choosestem cell treatment. Stem cells can help with the natural healing process of the body. They can also keep your painful shoulder condition from progressing and suppress inflammation that can make injuries more painful.

Injuries and medical conditions can cause various ankle and foot pains. For example, you can get injured while running in an uneven plane in Providence, R.I. Severe foot pain can hamper your mobility and interfere with your daily activities.

Sometimes, nonsurgical treatments are not enough to treat severe ankle or foot pain. A doctor may subsequently recommend surgery as treatment. However, surgical procedures may cause complications, such as blood clots, infections, or muscle loss. Stem cell treatment is a viable alternative if you want to avoid surgery.

Elbow pain can limit your movement. Additionally, living in pain may require you to make drastic lifestyle changes. Surgeries can cure various elbow pain issues. However, you need to go through physical rehabilitation for up to 6 months as part of the recovery process.

Stem cell treatment is a reliable alternative in treating elbow pain naturally. We aspirate stem cells from bone marrow. After that, we can inject stem cells and platelet-rich plasma into the affected area. Normally, one stem cell treatment can address various elbow problems.

Medications and drug injections are some common ways of treating spine or back pain. Surgery is another viable procedure as well. However, if you are not comfortable with undergoing surgery, then consider some alternatives. Stem cell treatment can help heal affected joints, generate new tissue, and prevent further inflammation.

Strains, tears, and contusions may cause various skeletal muscle injuries. Nonsurgical procedures can treat muscle pain. Doctors may also recommend surgery in case nonsurgical procedures dont work.

In case you dont want to get surgery, there are other options available. Stem cell treatment can help cure tendon or muscle pain. This treatment can also promote muscle repair and speed up your recovery.

Medical conditions, injuries, or accidents may cause pain in your hands or wrists. Sometimes, doctors may recommend surgery to treat various conditions. If you are not comfortable with surgery, then you can opt for stem cell treatment. Improve mobility, speed up recovery, and minimize pain with the help of stem cell treatment.

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Stem Cell Treatment Rhode Island - Boston Stem Cell Center

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Colorado Stem Cell Therapy | Home

Posted: October 1, 2018 at 11:44 pm

Select a Problem Area

If you have pain, we're here to help. Regenexx Procedures are patented stem cell and blood platelet procedures that are used to treat a wide range of joint and spine conditions.

Click a problem area to discover what Regenexx can do for you.

The Regenexx family of non-surgical stem-cell & blood platelet procedures are next generation regenerative injection treatments for those who are suffering from shoulder pain due to arthritis, rotator cuff and shoulder labrum tears, overuse injuries, and other degenerative conditions. Regenexx is also a viable alternative for those considering shoulder replacement surgery.

View Details About Shoulder Treatments

Commonly Treated Conditions:

Shoulder Procedure Video

Regenexx Procedures are advanced stem cell and blood platelet procedures for foot and ankle conditions. Before you consider ankle surgery, fusion or replacement, consider the worlds leading stem cell and prp injection treatments.

View Details About Foot & Ankle Treatments

Commonly Treated Conditions:

Ankle Procedure Video

The Regenexx family of non-surgical stem-cell & blood platelet procedures are next generation regenerative injection treatments for those who are suffering from pain or reduced range of motion due to basal joint / cmc arthritis, hand arthritis, or other injuries & conditions in the hand.

View Details About Hand & Wrist Treatments

Commonly Treated Conditions:

The Regenexx family of non-surgical stem cell and blood platelet procedures offer next-generation injection treatments for those who are suffering from knee pain or may be facing knee surgery or knee replacement due to common injuries, arthritis, overuse and other conditions.

View Details About Knee Treatments

Commonly Treated Conditions:

ACL Procedure VideoIn-Depth with Dr. John Schultz ACL Procedure Video

The Regenexx family of non-surgical stem-cell & blood platelet procedures are next generation regenerative injection treatments for those who are suffering from pain, inflammation or reduced range of motion due tocommon elbow injuries, arthritis and overuse conditions.

View Details About Elbow Treatments

Commonly Treated Conditions:

The Regenexx family of hip surgery alternatives are breakthrough, non-surgical stem-cell treatments for people suffering from hip pain due to common injuries, hip arthritis & other degenerative problems related to the hip joint.

View Details About Hip Treatments

Commonly Treated Conditions:

Hip Labrum Procedure Video Hip Avascular Necrosis Procedure Video

Regenexx has many non-surgical platelet and stem cell based procedures developed to help patients avoid spine surgery and high dose epidural steroid side effects. These procedures utilize the patients own natural growth factors or stem cells to treat bulging or herniated discs, degenerative conditions in the spine, and other back and neck conditions that cause pain.

View Details About Spine Treatments

Commonly Treated Conditions:

Intradiscal Procedure Video

Regenexx has many non-surgical platelet and stem cell based procedures developed to help patients avoid spine surgery and high dose epidural steroid side effects. These procedures utilize the patients own natural growth factors or stem cells to treat bulging or herniated discs, degenerative conditions in the spine, and other back and neck conditions that cause pain.

View Details About Spine Treatments

Commonly Treated Conditions:

Cervical Spine Video

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Colorado Stem Cell Therapy | Home

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New York & New Jersey – Stem Cell Therapy & Platelet Rich …

Posted: July 24, 2018 at 2:42 am

Select a Problem Area

If you have pain, we're here to help. Regenexx Procedures are patented stem cell and blood platelet procedures that are used to treat a wide range of joint and spine conditions.

Click a problem area to discover what Regenexx can do for you.

The Regenexx family of non-surgical stem-cell & blood platelet procedures are next generation regenerative injection treatments for those who are suffering from shoulder pain due to arthritis, rotator cuff and shoulder labrum tears, overuse injuries, and other degenerative conditions. Regenexx is also a viable alternative for those considering shoulder replacement surgery.

View Details About Shoulder Treatments

Commonly Treated Conditions:

Shoulder Procedure Video

Regenexx Procedures are advanced stem cell and blood platelet procedures for foot and ankle conditions. Before you consider ankle surgery, fusion or replacement, consider the worlds leading stem cell and prp injection treatments.

View Details About Foot & Ankle Treatments

Commonly Treated Conditions:

Ankle Procedure Video

The Regenexx family of non-surgical stem-cell & blood platelet procedures are next generation regenerative injection treatments for those who are suffering from pain or reduced range of motion due to basal joint / cmc arthritis, hand arthritis, or other injuries & conditions in the hand. View Details About Hand & Wrist Treatments Commonly Treated Conditions:

The Regenexx family of non-surgical stem cell and blood platelet procedures offer next-generation injection treatments for those who are suffering from knee pain or may be facing knee surgery or knee replacement due to common injuries, arthritis, overuse and other conditions.

View Details About Knee Treatments

Commonly Treated Conditions:

ACL Procedure VideoIn-Depth with Dr. John Schultz ACL Procedure Video

The Regenexx family of non-surgical stem-cell & blood platelet procedures are next generation regenerative injection treatments for those who are suffering from pain, inflammation or reduced range of motion due tocommon elbow injuries, arthritis and overuse conditions.

View Details About Elbow Treatments

Commonly Treated Conditions:

The Regenexx family of hip surgery alternatives are breakthrough, non-surgical stem-cell treatments for people suffering from hip pain due to common injuries, hip arthritis & other degenerative problems related to the hip joint.

View Details About Hip Treatments

Commonly Treated Conditions:

Hip Labrum Procedure Video Hip Avascular Necrosis Procedure Video

Regenexx has many non-surgical platelet and stem cell based procedures developed to help patients avoid spine surgery and high dose epidural steroid side effects. These procedures utilize the patients own natural growth factors or stem cells to treat bulging or herniated discs, degenerative conditions in the spine, and other back and neck conditions that cause pain.

View Details About Spine Treatments

Commonly Treated Conditions:

Intradiscal Procedure Video

Regenexx has many non-surgical platelet and stem cell based procedures developed to help patients avoid spine surgery and high dose epidural steroid side effects. These procedures utilize the patients own natural growth factors or stem cells to treat bulging or herniated discs, degenerative conditions in the spine, and other back and neck conditions that cause pain.

View Details About Spine Treatments

Commonly Treated Conditions:

Cervical Spine Video

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New York & New Jersey - Stem Cell Therapy & Platelet Rich ...

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