“…Developing injectable hydrogels for tissue regeneration is of great interest given the utility of injectable systems and their ease of translation in a clinical setting [ 2 , 6 , 32 ]. Materials that possess the ability to dual-gel through both physical and chemical gelation are particularly powerful as thermal gelation can be leveraged to space-fill and set the material inside a defect, while chemical crosslinking can be employed to lock the network in place to prevent syneresis.…”
Section: Resultsmentioning
confidence: 99%
“…We have demonstrated the ability to conjugate azide-modified N-cadherin mimic peptide HAV, osteogenic peptides GHK, BMHP1 and BMPm, as well as chondroitin sulfate [ 5 , 9 ]. This presentation of bioactive factors made possible via PdBT has demonstrated the ability to promote chondrogenic and osteogenic tissue growth in vitro and in vivo [ 5 , 6 ]. However, a mechanistic understanding of the impact of bioactive factor conjugation on the physicochemical properties of hydrogels is a gap in our understanding.…”
Thermogelling hydrogels such as poly(N-isopropyl acrylamide) (P(NiPAAm)) provide tunable constructs leveraged in many regenerative biomaterial applications. Recently, our lab developed the crosslinker poly(glycolic acid)-poly(ethylene glycol)-poly(glycolic acid)-di(but-2-yne-1,4-dithiol) (PdBT), which crosslinks P(NiPAAm-co-glycidyl methacrylate) via thiol-epoxy reaction and can be functionalized with azide-terminated peptides via alkyne-azide click chemistry. This study’s aim was to evaluate the impact of peptides on the physicochemical properties of the hydrogels. The physicochemical properties of the hydrogels including the lower critical solution temperature, crosslinking times, swelling, degradation, peptide release, and cytocompatibility were evaluated. The gels bearing peptides increased equilibrium swelling indicating hydrophilicity of the hydrogel components. Comparable sol fractions were found for all groups, indicating that inclusion of peptides does not impact crosslinking. Moreover, the inclusion of a matrix metalloproteinase (MMP)-sensitive peptide allowed elucidation of whether release of peptides from the network was driven by hydrolysis or enzymatic cleavage. The hydrophilicity of the network determined by the swelling behavior was demonstrated to be the most important factor in dictating hydrogel behavior over time. This study demonstrates the importance of characterizing the impact of additives on the physicochemical properties of hydrogels. These characteristics are key in determining design considerations for future in vitro and in vivo studies for tissue regeneration.
“…Developing injectable hydrogels for tissue regeneration is of great interest given the utility of injectable systems and their ease of translation in a clinical setting [ 2 , 6 , 32 ]. Materials that possess the ability to dual-gel through both physical and chemical gelation are particularly powerful as thermal gelation can be leveraged to space-fill and set the material inside a defect, while chemical crosslinking can be employed to lock the network in place to prevent syneresis.…”
Section: Resultsmentioning
confidence: 99%
“…We have demonstrated the ability to conjugate azide-modified N-cadherin mimic peptide HAV, osteogenic peptides GHK, BMHP1 and BMPm, as well as chondroitin sulfate [ 5 , 9 ]. This presentation of bioactive factors made possible via PdBT has demonstrated the ability to promote chondrogenic and osteogenic tissue growth in vitro and in vivo [ 5 , 6 ]. However, a mechanistic understanding of the impact of bioactive factor conjugation on the physicochemical properties of hydrogels is a gap in our understanding.…”
Thermogelling hydrogels such as poly(N-isopropyl acrylamide) (P(NiPAAm)) provide tunable constructs leveraged in many regenerative biomaterial applications. Recently, our lab developed the crosslinker poly(glycolic acid)-poly(ethylene glycol)-poly(glycolic acid)-di(but-2-yne-1,4-dithiol) (PdBT), which crosslinks P(NiPAAm-co-glycidyl methacrylate) via thiol-epoxy reaction and can be functionalized with azide-terminated peptides via alkyne-azide click chemistry. This study’s aim was to evaluate the impact of peptides on the physicochemical properties of the hydrogels. The physicochemical properties of the hydrogels including the lower critical solution temperature, crosslinking times, swelling, degradation, peptide release, and cytocompatibility were evaluated. The gels bearing peptides increased equilibrium swelling indicating hydrophilicity of the hydrogel components. Comparable sol fractions were found for all groups, indicating that inclusion of peptides does not impact crosslinking. Moreover, the inclusion of a matrix metalloproteinase (MMP)-sensitive peptide allowed elucidation of whether release of peptides from the network was driven by hydrolysis or enzymatic cleavage. The hydrophilicity of the network determined by the swelling behavior was demonstrated to be the most important factor in dictating hydrogel behavior over time. This study demonstrates the importance of characterizing the impact of additives on the physicochemical properties of hydrogels. These characteristics are key in determining design considerations for future in vitro and in vivo studies for tissue regeneration.
“…Furthermore, osteogenic and chondrogenic differentiation inducers, small molecules, and tissue-specific peptides were added into the bone and cartilage phase of a bi-layered hydrogel scaffold to further induce biphasic differentiation in osteochondral defect repairing ( Fig. 4 ) [ 62 , 63 ]. Fig.…”
Section: Articular Cartilage Regeneration Under Abnormal Conditionsmentioning
The development of interdisciplinary biomedical engineering brings significant breakthroughs to the field of cartilage regeneration. However, cartilage defects are considerably more complicated in clinical conditions, especially when injuries occur at specific sites (
e.g.
, osteochondral tissue, growth plate, and weight-bearing area) or under inflammatory microenvironments (
e.g.
, osteoarthritis and rheumatoid arthritis). Therapeutic implantations, including advanced scaffolds, developed growth factors, and various cells alone or in combination currently used to treat cartilage lesions, address cartilage regeneration under abnormal conditions. This review summarizes the strategies for cartilage regeneration at particular sites and pathological microenvironment regulation and discusses the challenges and opportunities for clinical transformation.
“…The system is fabricated by conjugating the polymeric hydrogel crosslinker, poly (glycolic acid)-poly (ethylene glycol)-poly (glycolic acid)-di(but-2-yne-1,4-dithiol) (PdBT), with chondrogenic N-cadherin mimetic peptide (GGGHAVDI) and osteogenic GHK peptide (GGGGHKSP), followed by mixing MSCs at physiological temperature. After a 12-week implantation in rabbit femoral condyle defects, the hydrogel system with N-cadherin mimetic peptide is associated with significantly higher histological measures of overall defect filling, cartilage surface regularity, GAGs/cell content in newly formed and adjacent cartilage compared to control [ 122 ]. Their results establish the utility of the functionalized bi-layered hydrogel system for the repair of the osteochondral defects.…”
Section: Bioactive Peptide To Promote Chondrogenesismentioning
confidence: 99%
“… Category Sub-category Name Origin Acid sequence Molecular mechanisms Refs. Growth factor derived peptide BMP signaling-derived peptide CK2.1 The amino acid residues 466–469 of BMPR-IA SYED Inhibition of the CK2-BMPR-IA interaction led to the activation of the Smad signaling pathway [ 99 , 104 ] BMP peptide The amino acid residues 73–92 of the knuckle epitope of BMP-2 KIPKASSVPTELSAISTLYL Activation of the BMP signaling pathway through BMP type I and type II receptors [ 101 , 104 , 165 ] B2A The amino acid residues 91–105 of BMP-2; heparin-binding motif AISMLYLDENEKVVL; RKRKLERIAR Activation of the ERK1/2, while inhibition p -Smad1/5/8 through binding to BMPR-IB and ActR-II [ 38 , 109 ] TGF-β derived peptide SPPEPS The latency-associated protein region in TGF-β3 SPPEPS Activation Insulin signaling pathways through GSK-3β [ 110 ] Extracellular matrix (ECM)-derived peptide Cell-cell adhesion molecule-derived peptide N-cadherin mimetic peptide N-cadherin contains a His-Ala-Val (HAV) sequence Ac-HAVDIGGGC; Ac-HAVDIGGKLDLKLDLKLDL; GGGHAVDI Suppression of canonical Wnt signaling by increasing GSK-3β, then GSK-3β-mediated degradation of β-catenin/LEF-1/TCF complex [ 41 , 53 , 118 , 121 , 122 ] …”
Section: Bioactive Peptide To Promote Chondrogenesismentioning
The repair of articular cartilage defects is still challenging in the fields of orthopedics and maxillofacial surgery due to the avascular structure of articular cartilage and the limited regenerative capacity of mature chondrocytes. To provide viable treatment options, tremendous efforts have been made to develop various chondrogenically-functionalized biomaterials for cartilage tissue engineering. Peptides that are derived from and mimic the functions of chondroconductive cartilage extracellular matrix and chondroinductive growth factors, represent a unique group of bioactive agents for chondrogenic functionalization. Since they can be chemically synthesized, peptides bear better reproducibility, more stable efficacy, higher modifiability and yielding efficiency in comparison with naturally derived biomaterials and recombinant growth factors. In this review, we summarize the current knowledge in the designs of the chondroinductive/chondroconductive peptides, the underlying molecular mechanisms and their-functionalized biomaterials for cartilage tissue engineering. We also systematically compare their
in-vitro
and
in-vivo
efficacies in inducing chondrogenesis. Our vision is to stimulate the development of novel peptides and their-functionalized biomaterials for cartilage tissue engineering.
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