Daniel Grande - Academia.edu (original) (raw)
Papers by Daniel Grande
Zenodo (CERN European Organization for Nuclear Research), Apr 9, 2020
Articular cartilage lesions caused by traumatic or age-dependent injuries are a major burden to p... more Articular cartilage lesions caused by traumatic or age-dependent injuries are a major burden to patients and the healthcare system, often requiring painful surgical procedures and long convalescence periods. We have developed a human extracellular matrix-based treatment that leverages the proteins and glycosaminoglycans secreted by hypoxia-induced multipotent cells to create a biological scaffold for the repair and regeneration of hyaline cartilage. Using three established animal models of articular cartilage injury, we evaluated if the human extracellular matrix formulation applied to experimentally induced osteochondral defects was able to improve the healing process as evidenced by visual inspection and histological evaluation. While untreated control groups showed defects characterized by fibrous tissue and suboptimal bone and cartilage regeneration, the animal subjects including rats, rabbits and goats that received the human-derived extracellular matrix treatment induced pronounced tissue regeneration of vascularized subchondral bone and an overlying proteoglycan-rich articular cartilage layer at the site of the defects. The results reported here demonstrate that the bioengineered human extracellular matrix functions as a potential human-source, chondroconducive matrix that supports bone and hyaline articular cartilage regeneration for the use in clinical orthopedic applications.
Bioelectronic Medicine, 2021
There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues t... more There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit “Technology targeting molecular mechanisms” took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare. The meeting was an arena for exchanging new ideas and seeding potential collaborations involving teams in academia and industry. The summit provided a forum for leaders in the field to discuss current progress, challenges, and future developments in Bioelectronic Medicine. The main topics discussed at the summit are outlined here.
Open journal of regenerative medicine, 2015
Background: Currently, there is no set standard treatment for long-segment tracheomalacia and ste... more Background: Currently, there is no set standard treatment for long-segment tracheomalacia and stenosis. In this study we set out to explore the potential to create a tissue engineered, biodegradable and three-dimensionally (3D) printed tracheal ring as a first step towards bioengineering a long segment tracheal replacement. Method of Approach: A 3D-Computer aided design (CAD) model was produced with multiple channels to allow for cellular growth while mimicking the native anatomy. The design was optimized to allow for printability, cellular expansion, and integration and 3D printed using a modified commercial 3D printer. Results: The cells grown in the scaffold demonstrated a similar proliferation trend compared to control. Chondrocytes within the 3D printed ring retained their phenotypic properties and did not infer any significant change in flexibility, contour and strength to the scaffold. Conclusion: The combination of living cells and a 3D modeled patient specific graft may address some of the unmet clinical needs in the field of tracheal reconstruction. This proof of concept study represents a first step towards producing a 3D printed and tissue engineered long segment tracheal replacement graft for airway surgery.
Open journal of regenerative medicine, 2015
Background: Currently, there is no set standard treatment for long-segment tracheomalacia and ste... more Background: Currently, there is no set standard treatment for long-segment tracheomalacia and stenosis. In this study we set out to explore the potential to create a tissue engineered, biodegradable and three-dimensionally (3D) printed tracheal ring as a first step towards bioengineering a long segment tracheal replacement. Method of Approach: A 3D-Computer aided design (CAD) model was produced with multiple channels to allow for cellular growth while mimicking the native anatomy. The design was optimized to allow for printability, cellular expansion, and integration and 3D printed using a modified commercial 3D printer. Results: The cells grown in the scaffold demonstrated a similar proliferation trend compared to control. Chondrocytes within the 3D printed ring retained their phenotypic properties and did not infer any significant change in flexibility, contour and strength to the scaffold. Conclusion: The combination of living cells and a 3D modeled patient specific graft may address some of the unmet clinical needs in the field of tracheal reconstruction. This proof of concept study represents a first step towards producing a 3D printed and tissue engineered long segment tracheal replacement graft for airway surgery.
International Journal of Molecular Sciences
Mesenchymal stem cell (MSC)-based exosomes have garnered attention as a viable therapeutic for po... more Mesenchymal stem cell (MSC)-based exosomes have garnered attention as a viable therapeutic for post-traumatic cartilage injury and osteoarthritis of the knee; however, efforts for application have been limited due to issues with variable dosing and rapid clearance in vivo. Scaffolds laden with MSC-based exosomes have recently been investigated as a solution to these issues. Here, we review in vivo studies and highlight key strengths and potential clinical uses of exosome–scaffold therapeutics for treatment of post-traumatic cartilage injury and osteoarthritis. In vivo animal studies were gathered using keywords related to the topic, revealing 466 studies after removal of duplicate papers. Inclusion and exclusion criteria were applied for abstract screening and full-text review. Thirteen relevant studies were identified for analysis and extraction. Three predominant scaffold subtypes were identified: hydrogels, acellular extracellular matrices, and hyaluronic acid. Each scaffold–exos...
Open Journal of Regenerative Medicine
Orthobiologics is a subset of regenerative medicine, which focuses on treating the musculoskeleta... more Orthobiologics is a subset of regenerative medicine, which focuses on treating the musculoskeletal system. The main therapeutics utilized include plateletrich plasma, stem cells, exosomes, and scaffolding matrices. Continuous discoveries and new innovations have led to an increase in both popularity and usage of these therapeutics by various medical and scientific communities. Despite its potential, however, the field is viewed with significant skepticism secondary to poor documentation, a lack of standardization, vague nomenclature, disorganized research protocols, and an absence of a clear understanding of the mechanisms underlying the effects of the various therapeutics. This ambiguity led to a surge in direct-to-consumer marketing by "Stem Cell Clinics", putting patient's health at risk and further delegitimizing the field. These shortcomings led to a recent push for standardization by both professionals and organizations alike; a move that has put Orthobiologics on the path toward becoming a guideline-driven, protocol-based, and researchbacked specialty. And with these rapid changes comes the need for an updated definition of "Orthobiologics", a crucial element of any legitimate and standardized medical field.
Ribosomopathies are a class of disorders caused by defects in the structure or function of the ri... more Ribosomopathies are a class of disorders caused by defects in the structure or function of the ribosome and characterized by tissue-specific abnormalities. Diamond Blackfan anemia (DBA) arises from different mutations, predominantly in genes encoding ribosomal proteins (RPs). Apart from the anemia, skeletal defects are among the most common anomalies observed in patients with DBA, but they are virtually restricted to radial ray and other upper limb defects. What leads to these site-specific skeletal defects in DBA remains a mystery. Using a novel mouse model for RP haploinsufficiency, we observed specific, differential defects of the limbs. Using complementary in vitro and in vivo approaches, we demonstrate that reduced WNT signaling and subsequent increased β-catenin degradation in concert with increased expression of p53 contribute to mesenchymal lineage failure. We observed differential defects in the proliferation and differentiation of mesenchymal stem cells (MSCs) from the for...
Journal of Orthopaedic Surgery and Research, 2020
Background 5-Aminolevulinic acid (5-ALA), a fluorescent contrast agent, has been used for tumor p... more Background 5-Aminolevulinic acid (5-ALA), a fluorescent contrast agent, has been used for tumor paint and photodynamic therapy (PDT) for various tumors, but its use with soft tissue sarcomas is not well documented. Myxofibrosarcoma, a subtype of soft tissue sarcoma with a high local recurrence rate, may benefit from similar types of treatment. The purpose of this study was to analyze the effects of 5-ALA tumor paint and PDT on a myxofibrosarcoma cell line. Methods Tumor paint was assessed by exposing micromass pellets of human adipose-derived stromal (ADS) cells or myxofibrosarcoma (MUG-Myx1) cells to 5-ALA. Cell pellets were then visualized using a microscope at established excitation and emission wavelengths. Corrected total cell fluorescence was calculated per accepted protocols. Photodynamic therapy was similarly assessed by exposing ADS and MUG-Myx1 cells to 5-ALA, with subsequent analysis via flow cytometry and real-time confocal microscopy. Results The use of 5-ALA tumor pain...
American Journal of Obstetrics and Gynecology, 2019
and witnessed domestic violence (35% vs 8%; OR¼5.9; 95% CI 2.1-17.1; p<.001) were more prevalent ... more and witnessed domestic violence (35% vs 8%; OR¼5.9; 95% CI 2.1-17.1; p<.001) were more prevalent in the CPP group (Table 2). CONCLUSION: CPP patients are likely to have high numbers of ACEs. This suggests that CPP symptomatology may, in part, be a manifestation of childhood exposures. In turn, it may require reconsideration of current clinical treatment, and a multidisciplinary approach tailoring non-surgical and surgical management.
CARTILAGE, 2018
Objective To evaluate the effects of TRB-N0224, a chemically modified curcumin (CMC) with zinc bi... more Objective To evaluate the effects of TRB-N0224, a chemically modified curcumin (CMC) with zinc binding properties and improved pharmacokinetics, in a rabbit anterior cruciate ligament (ACL) transection injury–induced model of osteoarthritis (OA). Design Thirty-eight skeletally mature New Zealand white rabbits were studied in 4 groups: a sham with arthrotomy ( n = 6), control with ACL transection ( n = 6), and 2 treatment groups with ACL transection and administration of TRB-N0224 at low (25 mg/kg/day) ( n = 13) and high (50 mg/kg/day) ( n = 13) doses. After euthanization at 12 weeks, outcomes were measured by post-necropsy gross morphology, biomechanics, and cartilage and synovium histology. Rabbit blood ELISA quantified cytokine and matrix metalloproteinase (MMP) concentrations at 0, 4, 8, and 12 weeks. Results Both treatment doses had fewer distal femoral condyle erosive defects than the control; the low dose demonstrated a mean 78% decrease ( P < 0.01). Histologically, the low...
Cartilage, Jan 28, 2018
Objective Rats are an early preclinical model for cartilage tissue engineering, and a practical s... more Objective Rats are an early preclinical model for cartilage tissue engineering, and a practical species for investigating the effects of aging. However, rats may be a poor aging model for mesenchymal stem cells (MSCs) based on laboratory reports of a severe decline in chondrogenesis beyond young adulthood. Such testing has not been conducted with MSCs seeded in a scaffold, which can improve the propensity of MSCs to undergo chondrogenesis. Therefore, the objective of this study was to evaluate chondrogenesis of middle-aged rat MSCs encapsulated in agarose. Design MSCs from 14- to 15-month-old rats were expanded, seeded into agarose, and cultured in chondrogenic medium with or without 5% serum for 15 days. Samples were evaluated for cell viability and cartilaginous extracellular matrix (ECM) accumulation. Experiments were repeated using MSCs from 6-week-old rats. Results During expansion, middle-aged rat MSCs demonstrated a diminishing proliferation rate that was improved ~2-fold in ...
Osteoarthritis and Cartilage, 2017
interest in articular cartilage and 214 target genes in subchondral bone by next generation seque... more interest in articular cartilage and 214 target genes in subchondral bone by next generation sequencing (NGS). In principal component analysis (PCA), the relationships of miRNA expression in bone and cartilage were improved after ESWT. Global functional annotation showed that predicted targets were involved in cartilage development, inflammatory and immune response, ion binding, angiogenesis, cell adhesion, cell cycle, transcription and translation, gene expression, NTP binding, signal transduction, collagen fibril organization, apoptotic process, chondrocyte differentiation, cell differentiation, bone development as well as cell proliferation. The miRNAs profile and the target genes were comprehensively surveyed and compared in articular cartilage and subchondral bone of early OA knee before and after ESWT. Conclusions: Our study represents the direct assessment to date of miRNA expression profiling in early OA articular cartilage and subchondral bone. The results provide insights that could contribute to the development of new biomarkers and therapeutic strategies for OA changes and the treatment with ESWT.
CARTILAGE, 2017
Objective To establish whether a novel biomaterial scaffold with tunable degradation profile will... more Objective To establish whether a novel biomaterial scaffold with tunable degradation profile will aid in cartilage repair of chondral defects versus microfracture alone in vitro and in a rat model in vivo. Design In vitro—Short- and long-term degradation scaffolds were seeded with culture expanded articular chondrocytes or bone marrow mesenchymal stem cells. Cell growth and differentiation were evaluated with cell morphological studies and gene expression studies. In vivo—A microfracture rat model was used in this study to evaluate the repair of cartilage and subchondral bone with the contralateral knee serving as the empty control. The treatment groups include (1) empty osteochondral defect, (2) polycaprolactone copolymer–based polyester polyurethane–urea (PSPU-U) caffold short-term degradative profile, and (3) PSPU-U scaffold long-term degradative profile. After placement of the scaffold, the rats were then allowed unrestricted activity as tolerated, and histological analyses were...
Journal of Trauma: Injury, Infection & Critical Care, 2009
Background-Hemorrhage is a common cause of death despite the recent advances in resuscitation and... more Background-Hemorrhage is a common cause of death despite the recent advances in resuscitation and critical care. Conventional resuscitation fluids are designed to reestablish tissue perfusion, but they fail to prevent systemic inflammation. Indeed, resuscitation can promote inflammatory responses, which can be more dangerous than the original hemorrhage. This consideration is relevant in critical care where hemorrhage is normally associated with collateral trauma that can exacerbate the inflammatory responses during resuscitation. Here, we analyzed whether ethyl pyruvate could provide a therapeutic antiinflammatory potential during resuscitation in experimental hemorrhage with trauma. Methods-Adult male Sprague-Dawley rats were subjected to trauma induced by closed femur fracture. Then, the animals were immediately subjected to lethal hemorrhage during 15 minutes to reach a mean arterial blood pressure of 35 mm Hg to 40 mm Hg and subsequent maintenance of this mean arterial blood pressure for another 15 minutes. Resuscitation was limited to 15 mL/kg Hextend with or without ethyl pyruvate. Results-Resuscitation with conventional fluids reestablished normal tissue perfusion, but still more than 60% of the animals died. Resuscitation with ethyl pyruvate protected all the animals from lethal hemorrhage with trauma. Trauma exacerbated tumor necrosis factor (TNF) levels in the serum, the spleen, and the heart. Ethyl pyruvate blunted TNF levels in the serum and all the organs but particularly in the lung and the liver during resuscitation. TNF levels in the lung, spleen, and the liver of those animals resuscitated with ethyl pyruvate were statistically similar to those in control animals. Conclusion-Ethyl pyruvate may attenuate systemic inflammatory responses during resuscitation and improve survival in experimental models of hemorrhage with trauma.
Biomaterials, 2000
It has been demonstrated that using cultured chondrocytes that have been seeded onto various biom... more It has been demonstrated that using cultured chondrocytes that have been seeded onto various biomatrices can enhance the quality of the articular cartilage repair tissue. As tissue-engineering becomes increasingly more complex there is a need to understand how a speci"c biomaterial may in#uence gene expression. In this study several commonly used sca!old materials for cartilage tissue engineering were evaluated with respect to their in#uence on matrix gene expression. Primary cultures of bovine chondrocytes were established in monolayer then seeded onto polylactic acid (PLLA), polyglycolic acid (PGA), collagen matrices. The induction of collagen type I, collagen type II, and aggrecan was observed at various time points on these biomaterials using RT}PCR. The collagen type I gene was upregulated on collagen sca!olds throughout the culture period. PLLA and PGA showed initial induction followed by downregulation. Monolayer culture did not induce collagen I message. Collagen II genes were selectively upregulated after 72 and 96 h post seeding depending the sca!old material. Monolayer culture had strong induction of collagen II. The aggrecan protein was consistently expressed in all sca!old materials cultures and monolayer.
Discovery medicine, 2011
Advancements in the technical aspects of tendon repair have significantly improved the treatment ... more Advancements in the technical aspects of tendon repair have significantly improved the treatment of tendon injuries. Arthroscopic techniques, suture material, and improved rehabilitation have all been contributing factors. Biological augmentation and tissue engineering appear to have the potential to improve clinical outcomes as well. After review of the physiology of tendon repair, three critical components of tissue engineering can be discerned: the cellular component, the carrier vehicle (matrix or scaffold), and the bioactive component (growth factors, platelet rich plasma). These three components are discussed with regard to each of three tendon types: Intra-synovial (flexor tendon), extra-synovial (Achilles tendon), and extra-synovial tendon under compression (rotator cuff). Scaffolds, biologically enhanced scaffolds, growth factors, platelet rich plasma, gene therapy, mesenchymal stem cells, and local environment factors in combination or alone may contribute to tendon healin...
Bioelectronic Medicine
Background Osteoarthritis (OA) is a common and debilitating condition characterized by degenerati... more Background Osteoarthritis (OA) is a common and debilitating condition characterized by degeneration of hyaline cartilage. Currently, there is no treatment for OA that directly targets degradation of cartilage matrix. Capacitively coupled electric fields (CCEFs) represent a noninvasive and cost-effective treatment modality that can potentially restore articular cartilage homeostasis. Previous studies showed that stimulation of articular cartilage with CCEFs resulted in upregulation of anabolic factors and downregulation of catabolic factors. These studies didn’t explain the derivation of the CCEFs or verify their uniformity and field strength, so it’s possible that cartilage wasn’t exposed to uniform field strength. The present study aims to employ CCEFs with verified uniform field strength in two in-vitro models of OA to investigate its potential to preserve cartilage matrix and validate the results of the aforementioned studies. Methods Rabbit hyaline chondrocytes and full-thicknes...
ASME 2012 Summer Bioengineering Conference, Parts A and B, 2012
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2014
The purpose of this study was to develop a novel method for creating an acellular bioactive scaff... more The purpose of this study was to develop a novel method for creating an acellular bioactive scaffold, to prove its efficacy in vivo and in vitro for the augmentation of biological repair, and to confirm that sonographic microscopy is a viable modality for monitoring the healing process of osteochondral defects implanted with preconditioned bioactive scaffolds. Rabbit marrow stromal cells were retrovirally transduced with either bone morphogenetic protein 7 (BMP-7) or insulinlike growth factor 1 (IGF-1) genes, cultured for 9 weeks in nonwoven poly-L-lactic acid scaffolds, and then frozen and lyophilized. The knees were evaluated at 3, 6, and 12 weeks after surgery using 20-MHz ultrasound and then prepared for routine histologic analysis. B-scans of the extracellular matrix defects were compared to histologic results. Control defects showed a void or a mixture of fibrocartilage tissue. Both types of scaffolds resulted in a higher percentage (both P< .001) of primarily hyaline carti...
Articular cartilage is highly acellular, with cell volume averaging only approximately 2% of the ... more Articular cartilage is highly acellular, with cell volume averaging only approximately 2% of the total cartilage volume in adults. The extracellular matrix is composed of a highly-complex network of collagen fibrils and proteoglycans. Type II collagen is the dominant collagen subtype found in cartilage. Clinically, current treatment options for cartilage defects can be categorized into cartilage stimulation and cartilage replacement strategies. Biological resurfacing of arthritic joints may soon become an alternative to total joint replacement. Mesenchymal stem cells (MSCs) capable of chondrogenesis are present in bone marrow, periosteum, synovium, and adipose tissue. Animal models have demonstrated the wide spectrum of clinical situations in which MSCs could have therapeutic effects. Transduced MSCs expressing IL-1Ra or antagonists of TNF may both enhance the reparative process through their inherent chondrogenic potential, and retard the degradative process in cartilage lesions. A...
Zenodo (CERN European Organization for Nuclear Research), Apr 9, 2020
Articular cartilage lesions caused by traumatic or age-dependent injuries are a major burden to p... more Articular cartilage lesions caused by traumatic or age-dependent injuries are a major burden to patients and the healthcare system, often requiring painful surgical procedures and long convalescence periods. We have developed a human extracellular matrix-based treatment that leverages the proteins and glycosaminoglycans secreted by hypoxia-induced multipotent cells to create a biological scaffold for the repair and regeneration of hyaline cartilage. Using three established animal models of articular cartilage injury, we evaluated if the human extracellular matrix formulation applied to experimentally induced osteochondral defects was able to improve the healing process as evidenced by visual inspection and histological evaluation. While untreated control groups showed defects characterized by fibrous tissue and suboptimal bone and cartilage regeneration, the animal subjects including rats, rabbits and goats that received the human-derived extracellular matrix treatment induced pronounced tissue regeneration of vascularized subchondral bone and an overlying proteoglycan-rich articular cartilage layer at the site of the defects. The results reported here demonstrate that the bioengineered human extracellular matrix functions as a potential human-source, chondroconducive matrix that supports bone and hyaline articular cartilage regeneration for the use in clinical orthopedic applications.
Bioelectronic Medicine, 2021
There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues t... more There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit “Technology targeting molecular mechanisms” took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare. The meeting was an arena for exchanging new ideas and seeding potential collaborations involving teams in academia and industry. The summit provided a forum for leaders in the field to discuss current progress, challenges, and future developments in Bioelectronic Medicine. The main topics discussed at the summit are outlined here.
Open journal of regenerative medicine, 2015
Background: Currently, there is no set standard treatment for long-segment tracheomalacia and ste... more Background: Currently, there is no set standard treatment for long-segment tracheomalacia and stenosis. In this study we set out to explore the potential to create a tissue engineered, biodegradable and three-dimensionally (3D) printed tracheal ring as a first step towards bioengineering a long segment tracheal replacement. Method of Approach: A 3D-Computer aided design (CAD) model was produced with multiple channels to allow for cellular growth while mimicking the native anatomy. The design was optimized to allow for printability, cellular expansion, and integration and 3D printed using a modified commercial 3D printer. Results: The cells grown in the scaffold demonstrated a similar proliferation trend compared to control. Chondrocytes within the 3D printed ring retained their phenotypic properties and did not infer any significant change in flexibility, contour and strength to the scaffold. Conclusion: The combination of living cells and a 3D modeled patient specific graft may address some of the unmet clinical needs in the field of tracheal reconstruction. This proof of concept study represents a first step towards producing a 3D printed and tissue engineered long segment tracheal replacement graft for airway surgery.
Open journal of regenerative medicine, 2015
Background: Currently, there is no set standard treatment for long-segment tracheomalacia and ste... more Background: Currently, there is no set standard treatment for long-segment tracheomalacia and stenosis. In this study we set out to explore the potential to create a tissue engineered, biodegradable and three-dimensionally (3D) printed tracheal ring as a first step towards bioengineering a long segment tracheal replacement. Method of Approach: A 3D-Computer aided design (CAD) model was produced with multiple channels to allow for cellular growth while mimicking the native anatomy. The design was optimized to allow for printability, cellular expansion, and integration and 3D printed using a modified commercial 3D printer. Results: The cells grown in the scaffold demonstrated a similar proliferation trend compared to control. Chondrocytes within the 3D printed ring retained their phenotypic properties and did not infer any significant change in flexibility, contour and strength to the scaffold. Conclusion: The combination of living cells and a 3D modeled patient specific graft may address some of the unmet clinical needs in the field of tracheal reconstruction. This proof of concept study represents a first step towards producing a 3D printed and tissue engineered long segment tracheal replacement graft for airway surgery.
International Journal of Molecular Sciences
Mesenchymal stem cell (MSC)-based exosomes have garnered attention as a viable therapeutic for po... more Mesenchymal stem cell (MSC)-based exosomes have garnered attention as a viable therapeutic for post-traumatic cartilage injury and osteoarthritis of the knee; however, efforts for application have been limited due to issues with variable dosing and rapid clearance in vivo. Scaffolds laden with MSC-based exosomes have recently been investigated as a solution to these issues. Here, we review in vivo studies and highlight key strengths and potential clinical uses of exosome–scaffold therapeutics for treatment of post-traumatic cartilage injury and osteoarthritis. In vivo animal studies were gathered using keywords related to the topic, revealing 466 studies after removal of duplicate papers. Inclusion and exclusion criteria were applied for abstract screening and full-text review. Thirteen relevant studies were identified for analysis and extraction. Three predominant scaffold subtypes were identified: hydrogels, acellular extracellular matrices, and hyaluronic acid. Each scaffold–exos...
Open Journal of Regenerative Medicine
Orthobiologics is a subset of regenerative medicine, which focuses on treating the musculoskeleta... more Orthobiologics is a subset of regenerative medicine, which focuses on treating the musculoskeletal system. The main therapeutics utilized include plateletrich plasma, stem cells, exosomes, and scaffolding matrices. Continuous discoveries and new innovations have led to an increase in both popularity and usage of these therapeutics by various medical and scientific communities. Despite its potential, however, the field is viewed with significant skepticism secondary to poor documentation, a lack of standardization, vague nomenclature, disorganized research protocols, and an absence of a clear understanding of the mechanisms underlying the effects of the various therapeutics. This ambiguity led to a surge in direct-to-consumer marketing by "Stem Cell Clinics", putting patient's health at risk and further delegitimizing the field. These shortcomings led to a recent push for standardization by both professionals and organizations alike; a move that has put Orthobiologics on the path toward becoming a guideline-driven, protocol-based, and researchbacked specialty. And with these rapid changes comes the need for an updated definition of "Orthobiologics", a crucial element of any legitimate and standardized medical field.
Ribosomopathies are a class of disorders caused by defects in the structure or function of the ri... more Ribosomopathies are a class of disorders caused by defects in the structure or function of the ribosome and characterized by tissue-specific abnormalities. Diamond Blackfan anemia (DBA) arises from different mutations, predominantly in genes encoding ribosomal proteins (RPs). Apart from the anemia, skeletal defects are among the most common anomalies observed in patients with DBA, but they are virtually restricted to radial ray and other upper limb defects. What leads to these site-specific skeletal defects in DBA remains a mystery. Using a novel mouse model for RP haploinsufficiency, we observed specific, differential defects of the limbs. Using complementary in vitro and in vivo approaches, we demonstrate that reduced WNT signaling and subsequent increased β-catenin degradation in concert with increased expression of p53 contribute to mesenchymal lineage failure. We observed differential defects in the proliferation and differentiation of mesenchymal stem cells (MSCs) from the for...
Journal of Orthopaedic Surgery and Research, 2020
Background 5-Aminolevulinic acid (5-ALA), a fluorescent contrast agent, has been used for tumor p... more Background 5-Aminolevulinic acid (5-ALA), a fluorescent contrast agent, has been used for tumor paint and photodynamic therapy (PDT) for various tumors, but its use with soft tissue sarcomas is not well documented. Myxofibrosarcoma, a subtype of soft tissue sarcoma with a high local recurrence rate, may benefit from similar types of treatment. The purpose of this study was to analyze the effects of 5-ALA tumor paint and PDT on a myxofibrosarcoma cell line. Methods Tumor paint was assessed by exposing micromass pellets of human adipose-derived stromal (ADS) cells or myxofibrosarcoma (MUG-Myx1) cells to 5-ALA. Cell pellets were then visualized using a microscope at established excitation and emission wavelengths. Corrected total cell fluorescence was calculated per accepted protocols. Photodynamic therapy was similarly assessed by exposing ADS and MUG-Myx1 cells to 5-ALA, with subsequent analysis via flow cytometry and real-time confocal microscopy. Results The use of 5-ALA tumor pain...
American Journal of Obstetrics and Gynecology, 2019
and witnessed domestic violence (35% vs 8%; OR¼5.9; 95% CI 2.1-17.1; p<.001) were more prevalent ... more and witnessed domestic violence (35% vs 8%; OR¼5.9; 95% CI 2.1-17.1; p<.001) were more prevalent in the CPP group (Table 2). CONCLUSION: CPP patients are likely to have high numbers of ACEs. This suggests that CPP symptomatology may, in part, be a manifestation of childhood exposures. In turn, it may require reconsideration of current clinical treatment, and a multidisciplinary approach tailoring non-surgical and surgical management.
CARTILAGE, 2018
Objective To evaluate the effects of TRB-N0224, a chemically modified curcumin (CMC) with zinc bi... more Objective To evaluate the effects of TRB-N0224, a chemically modified curcumin (CMC) with zinc binding properties and improved pharmacokinetics, in a rabbit anterior cruciate ligament (ACL) transection injury–induced model of osteoarthritis (OA). Design Thirty-eight skeletally mature New Zealand white rabbits were studied in 4 groups: a sham with arthrotomy ( n = 6), control with ACL transection ( n = 6), and 2 treatment groups with ACL transection and administration of TRB-N0224 at low (25 mg/kg/day) ( n = 13) and high (50 mg/kg/day) ( n = 13) doses. After euthanization at 12 weeks, outcomes were measured by post-necropsy gross morphology, biomechanics, and cartilage and synovium histology. Rabbit blood ELISA quantified cytokine and matrix metalloproteinase (MMP) concentrations at 0, 4, 8, and 12 weeks. Results Both treatment doses had fewer distal femoral condyle erosive defects than the control; the low dose demonstrated a mean 78% decrease ( P < 0.01). Histologically, the low...
Cartilage, Jan 28, 2018
Objective Rats are an early preclinical model for cartilage tissue engineering, and a practical s... more Objective Rats are an early preclinical model for cartilage tissue engineering, and a practical species for investigating the effects of aging. However, rats may be a poor aging model for mesenchymal stem cells (MSCs) based on laboratory reports of a severe decline in chondrogenesis beyond young adulthood. Such testing has not been conducted with MSCs seeded in a scaffold, which can improve the propensity of MSCs to undergo chondrogenesis. Therefore, the objective of this study was to evaluate chondrogenesis of middle-aged rat MSCs encapsulated in agarose. Design MSCs from 14- to 15-month-old rats were expanded, seeded into agarose, and cultured in chondrogenic medium with or without 5% serum for 15 days. Samples were evaluated for cell viability and cartilaginous extracellular matrix (ECM) accumulation. Experiments were repeated using MSCs from 6-week-old rats. Results During expansion, middle-aged rat MSCs demonstrated a diminishing proliferation rate that was improved ~2-fold in ...
Osteoarthritis and Cartilage, 2017
interest in articular cartilage and 214 target genes in subchondral bone by next generation seque... more interest in articular cartilage and 214 target genes in subchondral bone by next generation sequencing (NGS). In principal component analysis (PCA), the relationships of miRNA expression in bone and cartilage were improved after ESWT. Global functional annotation showed that predicted targets were involved in cartilage development, inflammatory and immune response, ion binding, angiogenesis, cell adhesion, cell cycle, transcription and translation, gene expression, NTP binding, signal transduction, collagen fibril organization, apoptotic process, chondrocyte differentiation, cell differentiation, bone development as well as cell proliferation. The miRNAs profile and the target genes were comprehensively surveyed and compared in articular cartilage and subchondral bone of early OA knee before and after ESWT. Conclusions: Our study represents the direct assessment to date of miRNA expression profiling in early OA articular cartilage and subchondral bone. The results provide insights that could contribute to the development of new biomarkers and therapeutic strategies for OA changes and the treatment with ESWT.
CARTILAGE, 2017
Objective To establish whether a novel biomaterial scaffold with tunable degradation profile will... more Objective To establish whether a novel biomaterial scaffold with tunable degradation profile will aid in cartilage repair of chondral defects versus microfracture alone in vitro and in a rat model in vivo. Design In vitro—Short- and long-term degradation scaffolds were seeded with culture expanded articular chondrocytes or bone marrow mesenchymal stem cells. Cell growth and differentiation were evaluated with cell morphological studies and gene expression studies. In vivo—A microfracture rat model was used in this study to evaluate the repair of cartilage and subchondral bone with the contralateral knee serving as the empty control. The treatment groups include (1) empty osteochondral defect, (2) polycaprolactone copolymer–based polyester polyurethane–urea (PSPU-U) caffold short-term degradative profile, and (3) PSPU-U scaffold long-term degradative profile. After placement of the scaffold, the rats were then allowed unrestricted activity as tolerated, and histological analyses were...
Journal of Trauma: Injury, Infection & Critical Care, 2009
Background-Hemorrhage is a common cause of death despite the recent advances in resuscitation and... more Background-Hemorrhage is a common cause of death despite the recent advances in resuscitation and critical care. Conventional resuscitation fluids are designed to reestablish tissue perfusion, but they fail to prevent systemic inflammation. Indeed, resuscitation can promote inflammatory responses, which can be more dangerous than the original hemorrhage. This consideration is relevant in critical care where hemorrhage is normally associated with collateral trauma that can exacerbate the inflammatory responses during resuscitation. Here, we analyzed whether ethyl pyruvate could provide a therapeutic antiinflammatory potential during resuscitation in experimental hemorrhage with trauma. Methods-Adult male Sprague-Dawley rats were subjected to trauma induced by closed femur fracture. Then, the animals were immediately subjected to lethal hemorrhage during 15 minutes to reach a mean arterial blood pressure of 35 mm Hg to 40 mm Hg and subsequent maintenance of this mean arterial blood pressure for another 15 minutes. Resuscitation was limited to 15 mL/kg Hextend with or without ethyl pyruvate. Results-Resuscitation with conventional fluids reestablished normal tissue perfusion, but still more than 60% of the animals died. Resuscitation with ethyl pyruvate protected all the animals from lethal hemorrhage with trauma. Trauma exacerbated tumor necrosis factor (TNF) levels in the serum, the spleen, and the heart. Ethyl pyruvate blunted TNF levels in the serum and all the organs but particularly in the lung and the liver during resuscitation. TNF levels in the lung, spleen, and the liver of those animals resuscitated with ethyl pyruvate were statistically similar to those in control animals. Conclusion-Ethyl pyruvate may attenuate systemic inflammatory responses during resuscitation and improve survival in experimental models of hemorrhage with trauma.
Biomaterials, 2000
It has been demonstrated that using cultured chondrocytes that have been seeded onto various biom... more It has been demonstrated that using cultured chondrocytes that have been seeded onto various biomatrices can enhance the quality of the articular cartilage repair tissue. As tissue-engineering becomes increasingly more complex there is a need to understand how a speci"c biomaterial may in#uence gene expression. In this study several commonly used sca!old materials for cartilage tissue engineering were evaluated with respect to their in#uence on matrix gene expression. Primary cultures of bovine chondrocytes were established in monolayer then seeded onto polylactic acid (PLLA), polyglycolic acid (PGA), collagen matrices. The induction of collagen type I, collagen type II, and aggrecan was observed at various time points on these biomaterials using RT}PCR. The collagen type I gene was upregulated on collagen sca!olds throughout the culture period. PLLA and PGA showed initial induction followed by downregulation. Monolayer culture did not induce collagen I message. Collagen II genes were selectively upregulated after 72 and 96 h post seeding depending the sca!old material. Monolayer culture had strong induction of collagen II. The aggrecan protein was consistently expressed in all sca!old materials cultures and monolayer.
Discovery medicine, 2011
Advancements in the technical aspects of tendon repair have significantly improved the treatment ... more Advancements in the technical aspects of tendon repair have significantly improved the treatment of tendon injuries. Arthroscopic techniques, suture material, and improved rehabilitation have all been contributing factors. Biological augmentation and tissue engineering appear to have the potential to improve clinical outcomes as well. After review of the physiology of tendon repair, three critical components of tissue engineering can be discerned: the cellular component, the carrier vehicle (matrix or scaffold), and the bioactive component (growth factors, platelet rich plasma). These three components are discussed with regard to each of three tendon types: Intra-synovial (flexor tendon), extra-synovial (Achilles tendon), and extra-synovial tendon under compression (rotator cuff). Scaffolds, biologically enhanced scaffolds, growth factors, platelet rich plasma, gene therapy, mesenchymal stem cells, and local environment factors in combination or alone may contribute to tendon healin...
Bioelectronic Medicine
Background Osteoarthritis (OA) is a common and debilitating condition characterized by degenerati... more Background Osteoarthritis (OA) is a common and debilitating condition characterized by degeneration of hyaline cartilage. Currently, there is no treatment for OA that directly targets degradation of cartilage matrix. Capacitively coupled electric fields (CCEFs) represent a noninvasive and cost-effective treatment modality that can potentially restore articular cartilage homeostasis. Previous studies showed that stimulation of articular cartilage with CCEFs resulted in upregulation of anabolic factors and downregulation of catabolic factors. These studies didn’t explain the derivation of the CCEFs or verify their uniformity and field strength, so it’s possible that cartilage wasn’t exposed to uniform field strength. The present study aims to employ CCEFs with verified uniform field strength in two in-vitro models of OA to investigate its potential to preserve cartilage matrix and validate the results of the aforementioned studies. Methods Rabbit hyaline chondrocytes and full-thicknes...
ASME 2012 Summer Bioengineering Conference, Parts A and B, 2012
Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2014
The purpose of this study was to develop a novel method for creating an acellular bioactive scaff... more The purpose of this study was to develop a novel method for creating an acellular bioactive scaffold, to prove its efficacy in vivo and in vitro for the augmentation of biological repair, and to confirm that sonographic microscopy is a viable modality for monitoring the healing process of osteochondral defects implanted with preconditioned bioactive scaffolds. Rabbit marrow stromal cells were retrovirally transduced with either bone morphogenetic protein 7 (BMP-7) or insulinlike growth factor 1 (IGF-1) genes, cultured for 9 weeks in nonwoven poly-L-lactic acid scaffolds, and then frozen and lyophilized. The knees were evaluated at 3, 6, and 12 weeks after surgery using 20-MHz ultrasound and then prepared for routine histologic analysis. B-scans of the extracellular matrix defects were compared to histologic results. Control defects showed a void or a mixture of fibrocartilage tissue. Both types of scaffolds resulted in a higher percentage (both P< .001) of primarily hyaline carti...
Articular cartilage is highly acellular, with cell volume averaging only approximately 2% of the ... more Articular cartilage is highly acellular, with cell volume averaging only approximately 2% of the total cartilage volume in adults. The extracellular matrix is composed of a highly-complex network of collagen fibrils and proteoglycans. Type II collagen is the dominant collagen subtype found in cartilage. Clinically, current treatment options for cartilage defects can be categorized into cartilage stimulation and cartilage replacement strategies. Biological resurfacing of arthritic joints may soon become an alternative to total joint replacement. Mesenchymal stem cells (MSCs) capable of chondrogenesis are present in bone marrow, periosteum, synovium, and adipose tissue. Animal models have demonstrated the wide spectrum of clinical situations in which MSCs could have therapeutic effects. Transduced MSCs expressing IL-1Ra or antagonists of TNF may both enhance the reparative process through their inherent chondrogenic potential, and retard the degradative process in cartilage lesions. A...